@article {pmid41965687,
year = {2026},
author = {Hamed, FM and Mady, MS and Elgayed, SH and Mansour, YE and Mahgoub, S and Lai, KH and Lin, CY and Elsayed, HE and Moharram, FA},
title = {Carpoxylon macrospermum leaf extract and its phenolic compounds: a multi-targeted therapeutic remedy for Alzheimer's disease.},
journal = {BMC complementary medicine and therapies},
volume = {26},
number = {1},
pages = {},
pmid = {41965687},
issn = {2662-7671},
support = {MOST 111-2320-B-038-040-MY3, 113-2628-B-038-009-MY3, and 113-2321-B-255-001//National Science and Technology Council of Taiwan/ ; },
abstract = {BACKGROUND: Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder with a significant impact, especially on elderly people. Although no current treatment is available for AD, several studies have been conducted to discover alternative remedies capable of managing its symptoms and slowing the progression. Accordingly, herein we analysed the phenolic composition and investigated the defatted aqueous methanol extract (DAE) of Carpoxylon macrospermum H.Wendl. & Drude (Family Arecaceae) leaves against key enzymes in addition to oxidative and inflammatory markers involved in AD progression.

METHODS: NMR and mass spectrometry elucidated the phenolic compounds. Human carbonic anhydrase (hCA), human acetyl cholinesterase (AChE), and cyclo-oxygenase 2 (COX-2) inhibitor screening kits were used to assess the enzyme-inhibitory potential. Lipo-poly saccharide (LPS)-induced murine macrophage (RAW 264.7) in vitro model was used to test the anti-inflammatory effect. Molecular docking studies were conducted using AutoDock Vina.

RESULTS: Chlorogenic acid (1), rutin (2), hesperidin (3), vanillic acid (4), and p-hydroxybenzoic acid (5) have been isolated. The DAE and compounds 2 and 4 significantly inhibited hCA enzyme with IC50 equivalent to 0.160 ± 0.008, 0.243 ± 0.012, and 0.290 ± 0.015 µg/mL, and AChE enzyme with an IC50 corresponding to 3.732 ± 0.13, 0.868 ± 0.03, and 0.597 ± 0.02 µg/mL, respectively. Additionally, they demonstrated potent anti-inflammatory activity by inhibiting the COX-2 enzyme with IC50 values of 4.602 ± 0.17, 2.806 ± 0.10, and 0.849 ± 0.03 µg/mL, respectively. The DAE, 2 and 4 reduced IL-2 to 3.49 ± 0.12—7.018 ± 0.24 pg/mL; IL-4 to 6.019 ± 0.21–12.07 ± 0.41 pg/mL, and TNF-α to 323.65 ± 11.10–501.88 ± 17.21 pg/mL, respectively. Western blotting revealed a decrease in iNOS protein expression. Rutin showed improved docking scores (-8.92 and -7.92 kcal/mol) with AChE and hCA, while 100 ns Molecular Dynamc Simulations (MDS) showed that rutin maintained stable interactions with the proteins throughout the simulations.

CONCLUSION: C. macrospermum extract and its phenolics are promising candidates for AD management, though additional in vivo and clinical studies are needed.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12906-026-05365-8.},
}

@article {pmid42158158,
year = {2026},
author = {Pozuelo Moyano, B and Orgeta, V and von Gunten, A and Vandel, P and Ma, R and Stewart, R and Mueller, C},
title = {Late-life difficult-to-treat depression and dementia subtypes: a naturalistic cohort study using electronic health records.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1795874},
pmid = {42158158},
issn = {1664-0640},
abstract = {INTRODUCTION: Late-life difficult-to-treat depression (LL-DTD) and dementia frequently coexist in later life, but it remains unclear whether clinical and sociodemographic characteristics, as well as medication exposure patterns, differ across dementia subtypes among older adults with both conditions.

METHODS: We analysed anonymised electronic health records from a south London catchment area. We included patients aged ≥60 years at first recorded depression diagnosis with a dementia diagnosis. LL-DTD was defined as inadequate response to ≥2 antidepressant trials. Dementia diagnoses were classified as Alzheimer's disease (AD), vascular dementia (VD), mixed AD/VD, dementia with Lewy bodies (DLB), or other/unspecified dementia. Around the index depressive episode, we captured sociodemographics, depressive symptoms, physical comorbidity, and medication indicators. We used multivariate logistic regression to examine cross-sectional correlates distinguishing dementia subtypes (with AD as reference) within the LL-DTD and dementia sample. We conducted stratified analyses comparing non-AD versus AD dementia by the temporal order of dementia and depression diagnoses.

RESULTS: Among 890 older adults with LL-DTD and dementia, AD was the most common subtype (33.9%), followed by mixed AD/VD (22.5%), VD (22.2%), other/unspecified dementia (15.2%), and DLB (6.2%). Depressive symptom profiles and psychotropic treatment history were broadly similar across subtypes. Compared with AD, VD was associated with greater functional impairment, while greater physical comorbidity burden was more evident in VD and mixed AD/VD.

DISCUSSION: Somatic multimorbidity and functional impairment provided the clearest clinical separation between subgroups, while depressive symptom patterns and medication exposure appeared largely non-specific across dementia subtypes. This underscores the importance of multimorbidity and physical health burden in understanding heterogeneity of dementia outcomes in LL-DTD.},
}

@article {pmid42158310,
year = {2025},
author = {Jain, SK and Sharma, S and Singh, VK and Matreja, PS},
title = {Transplantation of human glial cells into murine brains: A systematic review of efficacy and safety in neurodegenerative disorders.},
journal = {Current journal of neurology},
volume = {24},
number = {2},
pages = {154-167},
pmid = {42158310},
issn = {2717-011X},
abstract = {Background: Neurodegenerative diseases impact millions of individuals globally. Over the years, brain research has predominantly focused on neurons, but attention is now shifting to glial cells, the brain's support cells, which play a vital role in neurodegenerative disorders. Therefore, glial cell transplantation represents a groundbreaking treatment approach for various neurodegenerative disorders, with the potential to restore neuronal function. We evaluated the evidence on the therapeutic effectiveness of human glial cell transplantation in neurodegenerative disorders. Methods: The literature review was performed in PubMed, Scopus, and Web of Science from 2000 to 2024. The authors independently reviewed the screened articles. The study outcomes on cell differentiation, long survival restoration of neuron function, and adverse outcomes were analyzed. Results: Study results highlight promising findings, including astrocytes improving motor function and slowing disease progression in neurodegenerative animal models through neurotrophic factor secretion and reduced inflammation. Similarly, microglia transplantation has demonstrated effectiveness in reducing α-synuclein toxicity in Parkinson's disease (PD), removing amyloid-β plaques in Alzheimer's disease (AD) models, and enhancing neuronal survival. Additionally, in demyelinating pathologies like multiple sclerosis (MS), oligodendrocyte transplantation promotes remyelination, restoring axonal conduction and enhancing functional outcomes. Cografting astrocytes with neuro progenitor cells significantly improved dopamine neuron engraftment and survival for at least 6 months post-transplantation. Conclusion: The transplantation of human glial cells offers promising therapeutic potential for neurodegenerative disorders, improving neuronal survival, restoring damaged circuits, and reducing disease progression.},
}

@article {pmid42159155,
year = {2026},
author = {Cummings, JL and Atri, A and Sano, M and Zetterberg, H and Scheltens, P and Knop, FK and Johannsen, P and Wichmann, CA and Abschneider, RM and Leon, T and Taylor, J and Feldman, HH},
title = {Plain language summary: the evoke(+) studies of semaglutide for early Alzheimer's disease.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/17582024.2026.2666332},
pmid = {42159155},
issn = {1758-2032},
}

@article {pmid42159271,
year = {2026},
author = {Shi, J and Du, Y and Wang, H and Zhang, N and Chen, W and Ni, J and Lu, X and Sun, Y and Wang, G and Liu, J and Zhang, W and Wei, M and Li, T and Zhou, B and Li, F and Wei, C and Yao, L and Xie, H and Tian, J and , },
title = {A paradigm of the diagnosis and treatment for the whole process of Alzheimer's disease.},
journal = {Annals of medicine},
volume = {58},
number = {1},
pages = {2672193},
doi = {10.1080/07853890.2026.2672193},
pmid = {42159271},
issn = {1365-2060},
mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy ; *Medicine, Chinese Traditional/methods ; Biomarkers ; Disease Progression ; Early Diagnosis ; Severity of Illness Index ; Practice Guidelines as Topic ; },
abstract = {INTRODUCTION: The clinical management of Alzheimer's disease (AD) is still constrained by the fact that its incompletely understood pathogenesis, difficulty in early diagnosis and the limited long-term treatment benefits so far. This article summarizes a regional perspective on the diagnosis and treatment of AD from the Alzheimer's Disease Chinese (ADC) guideline working group, aiming to improve the whole-process management of AD.

DISCUSSION: The article presents a comprehensive overview of a proposed diagnostic and therapeutic paradigm for AD, consisting of a three-dimensional diagnostic framework and a sequential therapy concept. Crucially, while biological biomarkers of AD are present at all stages, they may be unrelated to clinical severity. To address this, the diagnostic framework combines core clinical criteria with early-changing biomarkers, syndrome staging and traditional Chinese medicine (TCM)-based pattern phenotyping. This integrated, simplified and practical approach enhances diagnostic certainty and its correlation with clinical severity. This sequential therapy is a stage-adaptive treatment plan adjusted according to the disease progression, utilizing a dynamic, multi-target combination therapy. Unlike the existing unchanging single-target therapies, this approach provides specific mechanistic interventions tailored to each stage to prolong efficacy and delay disease progression.

CONCLUSIONS: This paradigm provides a whole-process, stage-oriented approach to AD diagnosis and management that may improve translational relevance, clinical applicability and continuity of care in real-world settings. Future cohort-based validation studies are needed to confirm its diagnostic performance and clinical benefits, and to refine its implementation.},
}

Humans
*Alzheimer Disease/diagnosis/therapy
*Medicine, Chinese Traditional/methods
Biomarkers
Disease Progression
Early Diagnosis
Severity of Illness Index
Practice Guidelines as Topic

@article {pmid42159313,
year = {2026},
author = {Tajika, A and Omae, K and Sahker, E and Luo, Y and Takekita, Y and Furukawa, TA},
title = {Public acceptance and expectations for Lecanemab: Insights from a Smallest Worthwhile Difference study.},
journal = {Psychiatry and clinical neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1111/pcn.70082},
pmid = {42159313},
issn = {1440-1819},
abstract = {AIM: To determine the smallest worthwhile difference (SWD) for lecanemab, a disease-modifying drug for Alzheimer's disease (AD), among the general Japanese population using a benefit-harm trade-off method.

METHODS: We conducted an online survey with 658 participants to evaluate their preferences for the treatment effect of lecanemab, given its associated risks and high cost. We calculated SWD as the minimum required increase in the possibility of maintaining cognitive function (relative to the 50% without lecanemab) that patients would accept in exchange for the burdens of treatment (adverse effects, costs, other inconveniences). We examined the median SWD for two scenarios: a family member (SWD-families) and others (SWD-others), and analyzed subgroup differences.

RESULTS: The median SWD revealed a 15% increase for SWD-families and SWD-others. This value exceeds the drug's actual efficacy of an 8% increase. Notably, 17% of respondents reported zero SWD, driven by an intense fear of AD and possibly high expectations from media coverage. Including these participants, nearly half of the respondents considered the current effect worthwhile. No noticeable difference was found between the SWD-families and SWD-others.

CONCLUSION: Based on Japanese clinical scenarios, the public's median expectation for lecanemab exceeds its efficacy, though its current benefit remains acceptable to nearly half the population. These findings underscore that the SWD is shaped by psychological drivers, including fear and hope, rather than just reasoned evaluation. Clinicians must manage these expectations, accounting for highly heterogeneous treatment preferences. Future research should account for emotional factors that can overshadow a rational assessment of treatment value.},
}

@article {pmid42160117,
year = {2026},
author = {Chen, H and Wang, T and Xia, K and Li, X and Yao, X and Huang, W},
title = {Emerging Nanoreactors for Precision Disease Treatment: From Principles to Biomedical Applications.},
journal = {Small (Weinheim an der Bergstrasse, Germany)},
volume = {},
number = {},
pages = {e73859},
doi = {10.1002/smll.73859},
pmid = {42160117},
issn = {1613-6829},
support = {BK20251864//Basic Research Program of Jiangsu/ ; 62288102//Natural Science Foundation of China/ ; //Disciplinary Fund of the School of Pharmaceutical Sciences/ ; 20250285//Nanjing Tech University Teaching Reform Project/ ; },
abstract = {Inspired by natural cellular compartments, nanoreactors are spatially confined nanostructures that precisely regulate chemical and biological reactions and act as high-performance catalytic nanocontainers. Multifunctional integration of these systems surmounts the inherent limitations of conventional therapeutic modalities. This review focuses on recent breakthroughs in organic and organic-inorganic hybrid nanoreactors, highlighting three core effects: (1) the spatial confinement effect, which elevates the reactant concentration, accelerates mass transfer, lowers activation energy, modulates electronic states, and boosts reaction rates by orders of magnitude; (2) the synergistic effect of active sites, which enables efficient cascade reactions via spatially segregated or hierarchical catalytic architectures; (3) the stimuli-responsive effect, which dynamically controls catalysis and cargo release under endogenous (pH, enzymes, ROS) or exogenous (light, temperature) cues. Typical nanoreactors (liposomes, polymeric micelles/vesicles, mesoporous silica, protein cages, and organic-inorganic hybrids) are systematically discussed regarding structural merits and biomedical applications in treating diabetes, rheumatoid arthritis (RA), chronic wound healing, cancer, and Alzheimer's disease (AD). Current challenges and future perspectives are also addressed. Intelligent nanoreactors are expected to offer immense potential for disease diagnosis and therapy.},
}

@article {pmid42160848,
year = {2026},
author = {Zheng, M and Yang, M and Su, W and Tian, L and Gao, W},
title = {Targeting microglia: A new strategy for the treatment of Alzheimer's disease.},
journal = {Journal of neuroimmunology},
volume = {418},
number = {},
pages = {578966},
doi = {10.1016/j.jneuroim.2026.578966},
pmid = {42160848},
issn = {1872-8421},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, and chronic neuroinflammation, remains without curative therapies. Emerging evidence underscores microglia, the brain's resident immune cells, as pivotal players in AD pathogenesis, exerting dual roles in neuroprotection and neurotoxicity. This review synthesizes current knowledge on microglial dynamics, including their heterogeneous activation states (e.g., disease-associated microglia), metabolic reprogramming, aging-related dysfunction, and subset heterogeneity, which collectively influence Aβ clearance, tau propagation, and synaptic integrity. We highlight the interplay between microglial receptors-such as TREM2, APOE, and neurotransmitter receptors (e.g., cholinergic, glutamatergic, and cannabinoid receptors)-and AD pathology, emphasizing their roles in modulating neuroinflammation, phagocytosis, and neuronal excitotoxicity. Furthermore, we evaluate therapeutic strategies targeting microglia, including pharmacologic modulation of neuroinflammatory pathways, metabolic interventions, and cell transplantation, which aim to restore homeostatic microglial functions. Challenges in clinical translation, such as temporal specificity of interventions and microglial plasticity, are critically discussed. By integrating recent advances in single-cell genomics and neuroimmunology, this review provides a roadmap for developing microglia-centric therapies to disrupt the vicious cycle of neuroinflammation and neurodegeneration in AD, offering novel insights for future research and therapeutic innovation.},
}

@article {pmid42160956,
year = {2026},
author = {Yan, Y and Hu, D and Kong, L and Li, K and Su, J and Wu, Y and Zhan, H and Zhang, H and Sun, Y and Dou, X and Huang, P and Zhou, J},
title = {Reductions in neuropsychiatric symptoms after lecanemab treatment and their associations with imaging markers of β-amyloid clearance.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {7},
pages = {100600},
doi = {10.1016/j.tjpad.2026.100600},
pmid = {42160956},
issn = {2426-0266},
abstract = {BACKGROUND: Anti-amyloid-β (Aβ) therapies can slow cognitive decline and reduce cerebral amyloid burden in Alzheimer's disease (AD). Neuropsychiatric symptoms (NPS) are highly prevalent across the disease course and substantially contribute to disability and caregiver burden. However, whether Aβ clearance translates into improvements in NPS remains unclear.

METHOD: We enrolled 144 individuals with AD-related mild cognitive impairment or AD dementia who received intravenous lecanemab infusions. Standardized clinical rating scales, including the Neuropsychiatric Inventory, and amyloid PET were assessed at baseline (V0), 6 months (V1), and 12 months (V2). Longitudinal changes in clinical function and amyloid burden were analyzed.

RESULTS: Lecanemab treatment was associated with robust reductions in amyloid PET biomarkers and significant short-term reductions in NPS scores in patients who completed follow-up. Longitudinal analyses showed that reductions in total NPI scores were significantly associated with amyloid-β clearance in the insular cortex. Reductions in the hyperactivity subsyndrome were associated with amyloid reduction across a broader network, including the frontal and temporal lobes, striatum, and insular cortex.

CONCLUSIONS: In this real-world cohort, lecanemab was associated with short-term reductions in NPS. Changes in NPS severity were linked to regional amyloid-β clearance.},
}

@article {pmid42161225,
year = {2026},
author = {McNamara, O and Delany, T and Kwakowsky, A},
title = {Bumetanide as a potential treatment for neurodegenerative and neurodevelopmental disorders: A systematic review.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {200},
number = {},
pages = {119533},
doi = {10.1016/j.biopha.2026.119533},
pmid = {42161225},
issn = {1950-6007},
abstract = {Neurological disorders represent a major global health burden, affecting an estimated 3.4 billion individuals worldwide. Bumetanide, a clinically approved loop-diuretic and antagonist of the Na[+] -K[+]-Cl[-] cotransporter NKCC1, has recently emerged as a candidate for repurposing in the treatment of neurological disorders. Disrupted excitation-inhibition balance, driven in part by depolarizing GABAA receptor signaling resulting from altered chloride homeostasis, has been implicated across multiple neurodegenerative and neurodevelopmental conditions. This systematic literature review evaluated preclinical and clinical evidence for the efficacy of bumetanide across a range of neurological disorders, including Alzheimer's, Parkinson's, and Huntington's disease, autism spectrum disorder, schizophrenia, tuberous sclerosis, fragile X syndrome, Down syndrome, and Angelman syndrome. Across in vivo and ex vivo models, bumetanide frequently restored hyperpolarizing GABAergic activity and attenuated behavioral and cognitive abnormalities, although translational relevance is constrained by limited central nervous system penetration following systemic administration. Clinical evidence mainly comes from autism spectrum disorder, where some studies have reported modest improvements in behavioral outcomes and measurable neurophysiological changes, although findings remain inconsistent. Collectively, these findings suggest that NKCC1 inhibition represents a mechanistically relevant but clinically unproven therapeutic strategy. Further research is required to clarify the cellular mechanisms underlying bumetanide responsiveness, optimize delivery to the central nervous system, and identify biomarkers to stratify patients most likely to respond to treatment.},
}

@article {pmid42161327,
year = {2026},
author = {Vallikivi, JK and Kooyman, M and , and Kirby, J and Nigel Leigh, P and Iacoangeli, A and Al-Chalabi, A and Al Khleifat, A},
title = {CYP2D6 variants in amyotrophic lateral sclerosis: an association study of risk and survival.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag178},
pmid = {42161327},
issn = {1460-2156},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited therapeutic options. Riluzole remains the only widely available disease-modifying treatment for ALS, yet its survival benefit is modest and likely to vary substantially between patients. Cytochrome P450 2D6 (CYP2D6), is a highly polymorphic enzyme that contributes to interindividual variability in the metabolism of many drugs. CYP2D6 is also expressed in the brain, and experimental and translational studies indicate that brain CYP2D activity can influence local metabolism of neuroactive compounds. Accordingly, CYP2D6 poor function variants have been examined as susceptibility modifiers in the development of other neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease, with heterogenous evidence; however, the role of CYP2D6 in ALS has not been established.},
}

@article {pmid42161537,
year = {2026},
author = {Fernández-Romero, L and Díez-Cirarda, M and Delgado-Alonso, C and Cabrera-Martin, MN and González-Rosa, JJ and Sanz-Nieto, C and Pérez-Macías, N and Balugo, P and Gómez-Ruiz, N and Matias-Guiu, J and Portolés-Pérez, A and Matias-Guiu, JA},
title = {Long-term effect of transcranial magnetic stimulation and transcranial electrical stimulation in primary progressive aphasia: study protocol for a randomised, double-blind clinical trial (RECONNECT-PLUS).},
journal = {BMJ open},
volume = {16},
number = {5},
pages = {e112999},
doi = {10.1136/bmjopen-2025-112999},
pmid = {42161537},
issn = {2044-6055},
mesh = {Humans ; Double-Blind Method ; *Transcranial Direct Current Stimulation/methods ; *Transcranial Magnetic Stimulation/methods ; *Aphasia, Primary Progressive/therapy ; Female ; Aged ; *Language Therapy/methods ; Male ; Randomized Controlled Trials as Topic ; Treatment Outcome ; Middle Aged ; },
abstract = {INTRODUCTION: Primary progressive aphasia (PPA) is a neurodegenerative syndrome associated with Alzheimer's disease and frontotemporal degeneration. Non-invasive brain stimulation (NIBS) is a promising treatment, especially associated with language therapy, but comparative efficacy and long-term effects between the different techniques (transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS)) remain unknown. The present study aims to investigate the effects of non-invasive brain stimulation, alone or associated (tDCS/TMS/tDCS plus TMS) combined with language therapy delivered during a period of 6 months, in the progression of language impairment in PPA, compared with sham stimulation combined with language therapy.

METHODS AND ANALYSIS: The study is a randomised, double-blinded, parallel, sham-controlled clinical trial. Patients with PPA in early stages (global Clinical Dementia Rating equal to or less than 1) are eligible. They are to be randomised to one of the four treatment arms of the study (active tDCS-active TMS, active tDCS-sham TMS, sham tDCS-active TMS, sham tDCS-sham TMS). All patients will receive language therapy immediately after each session of NIBS, for 6 months. The primary outcome is the Mini-Linguistic State Examination. The secondary outcomes are naming of trained items, Addenbrooke's Cognitive Examination, Interview for Deterioration in Daily Living Activities, Clinical Dementia Rating including behaviour and language domains, Neuropsychiatric Inventory and regional brain metabolism. Exploratory substudies will be conducted including blood biomarkers, quantitative electroencephalography and spontaneous speech assessment.

ETHICS AND DISSEMINATION: The study is registered (ClinicalTrials.gov: NCT07158216) and approved by the Ethics Committee of the Hospital Clinico San Carlos (code 25/309-IC_P_CE). Patients will be enrolled after signing an informed consent form. Study outcomes will be disseminated through presentations at scientific conferences, publications in peer-reviewed journals and other academic forums.

TRIAL REGISTRATION NUMBER: NCT07158216.},
}

Humans
Double-Blind Method
*Transcranial Direct Current Stimulation/methods
*Transcranial Magnetic Stimulation/methods
*Aphasia, Primary Progressive/therapy
Female
Aged
*Language Therapy/methods
Male
Randomized Controlled Trials as Topic
Treatment Outcome
Middle Aged

@article {pmid42161925,
year = {2026},
author = {Kim, DY and Kim, SM and Lee, C and Han, IO},
title = {O-GlcNAcylation reprograms microglial inflammatory states and attenuates Alzheimer's disease pathology.},
journal = {Cell death & disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41419-026-08862-3},
pmid = {42161925},
issn = {2041-4889},
support = {RS-2024-00346770//National Research Foundation of Korea (NRF)/ ; },
abstract = {Chronic neuroinflammation, primarily driven by microglia, is a hallmark and key contributor to Alzheimer's disease (AD) progression. O-GlcNAcylation, a nutrient-sensitive post-translational modification, has emerged as a key regulator of cellular stress and inflammation, yet its role in microglial activation in AD remains unclear. We observed that hippocampal tissue from AD patients exhibits a marked reduction in O-GlcNAcylation, accompanied by enhanced pro-inflammatory M1 microglial polarization, elevated NF-κB signaling, and NLRP3 inflammasome activation. In an LPS-induced neuroinflammation model exhibiting AD-relevant inflammatory and cognitive features, as well as in in vitro microglial cultures, LPS exposure led to a pronounced decrease in O-GlcNAcylation, particularly within Iba1-positive microglia. Systemic or in vitro treatment with glucosamine (GlcN) effectively restored O-GlcNAc levels, suppressed M1-associated inflammatory pathways, and promoted an anti-inflammatory M2 phenotype. Mechanistically, GlcN enhanced O-GlcNAcylation of NF-κB subunits p65 and c-Rel, limiting their nuclear translocation and downstream pro-inflammatory gene expression. Notably, GlcN treatment ameliorated LPS-induced memory deficits and neuronal loss in mice. Collectively, these findings suggest that O-GlcNAcylation acts as a modulatory regulator of microglial activation and neuroinflammation in AD, and that enhancing O-GlcNAcylation may represent a potential therapeutic strategy to preserve immune homeostasis and neuronal integrity.},
}

@article {pmid42162073,
year = {2026},
author = {Zamani, NISM and Hamezah, HS and Mediani, A and Ghazali, M and Sadikan, MZ and Jam, FA},
title = {Selective elimination of amyloid-β-induced senescent neuroblastoma cells by Moringa oleifera leaf extract.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-53311-y},
pmid = {42162073},
issn = {2045-2322},
support = {Fundamental Research Grant Scheme (FRGS/1/2024/SKK10/MUCM/02/1)//Ministry of Higher Education, Malaysia/ ; (MUCM-MRB/001/2024)//MUCM-MRB joint seed grant/ ; },
abstract = {Accumulation of senescent cells (SnCs) in the ageing brain contributes to Alzheimer's disease (AD) progression by secreting a senescence-associated secretory phenotype (SASP) that exacerbates neuroinflammation and neurodegeneration. Senolytic agents that selectively eliminate SnCs have emerged as a potential therapeutic strategy; however, safer natural alternatives remain underexplored. In this study, we aimed to investigate the senolytic potential of Moringa oleifera leaf extract (MOL) in an in vitro AD-senescence model using SH-SY5Y cells exposed to amyloid-β (Aβ1-42) oligomers. SH-SY5Y cells exposed to 20 µM Aβ oligomers exhibited a senescent phenotype, characterised by increased senescence-associated β-galactosidase (SA-β-gal) positivity and upregulated nuclear expression of p21, p16, and γH2AX. Treatment with 300 µg/mL MOL significantly reduced the number of cells expressing senescence-associated molecular markers and induced apoptosis in SnCs, while attenuating the secretion of pro-inflammatory SASP cytokines, including IL-8 and TNF-α. Overall findings suggest that MOL extract preferentially targets SnCs and mitigates SASP-associated inflammation. These results support the potential of MOL as a natural compound with senolytic activity and provide a foundation for further development into its therapeutic relevance in AD.},
}

@article {pmid42162487,
year = {2026},
author = {Singh, A and Denkinger, MN and Leuzy, A and Dieckhoff, K and Liu, J and Marques, TM and Monuki, E and Stark, C and Grill, JD and Hom, C and Sultzer, D and Doran, E and Lott, I and Wood, K and Gawronski, B and Gonzalez, L and Choudhury, P and Atri, A and Beach, TG and Serrano, GE and Sajjadi, SA and Van Keuren-Jensen, K and Reiman, EM and Head, E and Ashton, NJ},
title = {A plasma protein signature for cerebral amyloid angiopathy.},
journal = {Acta neuropathologica},
volume = {151},
number = {1},
pages = {},
pmid = {42162487},
issn = {1432-0533},
support = {U24 NS072026/NS/NINDS NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; contract 211002//Arizona Department of Health Services/ ; contracts 4001, 0011, 05-901 and 1001//Arizona Biomedical Research Commission/ ; },
mesh = {Humans ; *Cerebral Amyloid Angiopathy/blood/pathology/diagnosis ; Female ; Male ; Aged ; Biomarkers/blood ; Aged, 80 and over ; Middle Aged ; Alzheimer Disease ; Cohort Studies ; },
abstract = {Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder characterized by the deposition of amyloid-β (Aβ) in the walls of leptomeningeal and cortical blood vessels that increases risk of intracerebral hemorrhages and progressive cognitive decline. More than 90% of individuals with Alzheimer's disease (AD) exhibit some level of CAA. Notably, in the new era of disease-modifying treatments for AD, CAA is a significant risk factor for amyloid-related imaging abnormalities (ARIA), an adverse event associated with anti-amyloid treatments. Therefore, there is great need for accessible, reliable and accurate in vivo biomarkers (e.g., blood-based) to improve antemortem identification of CAA that would improve risk stratification and reduce symptomatic ARIA. In this study, we employed the Nucleic Acid-Linked Immuno-Sandwich Assay (NULISA™) central nervous system panel for exploratory biomarker quantification in antemortem plasma of participants with neuropathological assessments for CAA from the Banner Sun Health Research Institute Brain and Body Donation Program (N = 251) and independently validated in the University of California Irvine Alzheimer Disease Research Center cohort (N = 110). We evaluated the differential protein expression in antemortem plasma sample taken < 5 years (mean 1.76 ± 1.3) from death using a logistic regression model. We further compared multi-biomarker models and found that a combination of CRP, IL4, CCL11, NPY and PDLIM5, plus demographic covariates showed an area under the curve (AUC) of 0.90 (95% CI 0.86-0.94) to identify neuropathologically confirmed CAA in the discovery cohort. In our independent replication, the antemortem plasma signature performed better than the basic demographics model showing a potential to predict CAA. The exploration and validation in antemortem plasma indicate that a multi-analyte panel, when combined with in vivo blood biomarkers for AD pathology, may be capable of identifying the presence of CAA and could have an meaningful impact on the clinical evaluation of patients under the investigation for cognitive decline. Further developments in biomarkers for this condition are crucial so that CAA identification could inform treatment decisions by highlighting ARIA risk.},
}

Humans
*Cerebral Amyloid Angiopathy/blood/pathology/diagnosis
Female
Male
Aged
Biomarkers/blood
Aged, 80 and over
Middle Aged
Alzheimer Disease
Cohort Studies

@article {pmid42162953,
year = {2026},
author = {Karthivashan, G and Wang, S and Wu, Q and Dahal, A and Li, X and Galleguillos, D and Sipione, S and Thinakaran, G and Kar, S},
title = {Native PLGA nanoparticles attenuate disease pathology via multiple pathways in 5xFAD Alzheimer's model.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71348},
doi = {10.1002/alz.71348},
pmid = {42162953},
issn = {1552-5279},
support = {MOP-84480//CIHR/Canada ; PJT-175090//CIHR/Canada ; //Alzheimer Society of Alberta and Northwest Territories/ ; RF1AG077610//National Institute on Aging, National Institutes of Health/ ; RF1AG079141//National Institute on Aging, National Institutes of Health/ ; //Ballermann Translational Research Fellowship/ ; //SynAD postdoctoral fellowships/ ; },
mesh = {*Alzheimer Disease/pathology/drug therapy/metabolism ; Animals ; *Polylactic Acid-Polyglycolic Acid Copolymer/administration & dosage/pharmacology ; *Nanoparticles/administration & dosage ; Mice ; *Amyloid beta-Peptides/metabolism/drug effects ; Disease Models, Animal ; Male ; Mice, Transgenic ; Brain/pathology/metabolism/drug effects ; },
abstract = {INTRODUCTION: Elevated amyloid beta (Aβ) levels and aggregation contribute to neurotoxicity and development of Alzheimer's disease (AD), the leading cause of dementia in the elderly. While we reported that native poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles, clinically used in drug delivery, suppress Aβ aggregation/toxicity, their effects in adult 5xFAD mice with advanced Aβ pathology remain unknown.

METHODS: We evaluated the effects of native PLGA in 8-month-old male 5xFAD mice via chronic intracerebroventricular (ICV) infusion using mini osmotic pumps. Cognitive function, amyloid level/burden, synaptic integrity, and neurodegenerative events were assessed along with transcript levels in brain tissues using bulk RNA sequencing (RNA-seq).

RESULTS: PLGA treatment reversed cognitive deficits, reduced Aβ levels/deposits, and attenuated neurodegenerative events. These effects were associated with modulation of Aβ production, oxidative stress, and lysosomal Aβ clearance. RNA-seq revealed transcriptional changes related to vesicle trafficking, immune activity, and redox regulation.

DISCUSSION: Native PLGA, by targeting different facets of the Aβ axis, offer unique therapeutic potential in treating AD-related pathology.},
}

*Alzheimer Disease/pathology/drug therapy/metabolism
Animals
*Polylactic Acid-Polyglycolic Acid Copolymer/administration & dosage/pharmacology
*Nanoparticles/administration & dosage
Mice
*Amyloid beta-Peptides/metabolism/drug effects
Disease Models, Animal
Male
Mice, Transgenic
Brain/pathology/metabolism/drug effects

@article {pmid42162968,
year = {2026},
author = {Reyna, NC and Hamilton, DA},
title = {Effects of Corticotropin-Releasing Factor 1 Receptor Antagonism on In Vivo Dentate Gyrus Long-Term Potentiation in the TgF344-AD Rat Model of Alzheimer's Disease.},
journal = {Hippocampus},
volume = {36},
number = {3},
pages = {e70103},
doi = {10.1002/hipo.70103},
pmid = {42162968},
issn = {1098-1063},
support = {P20AG068077/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; *Long-Term Potentiation/drug effects/physiology ; *Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors/metabolism ; *Dentate Gyrus/drug effects/physiopathology ; *Alzheimer Disease/physiopathology/drug therapy/pathology/genetics ; *Pyrroles/pharmacology ; *Pyrimidines/pharmacology ; Disease Models, Animal ; CRF Receptor, Type 1 ; Rats, Transgenic ; Male ; Rats ; Rats, Inbred F344 ; Excitatory Postsynaptic Potentials/drug effects/physiology ; },
abstract = {Alzheimer's disease (AD) is characterized by irreversible neurobiological deterioration and cognitive impairment. AD patients exhibit stress system abnormalities including upregulation of the corticotropin releasing factor type 1 receptor (CRF1) and elevated cortisol. Psychological distress increases the likelihood of AD diagnosis and hastens neurocognitive decline. Administration of the CRF1 antagonist, Antalarmin, reduces AD pathogenesis and anxiety-like behavior in models of AD. Motivated by these observations, the current study examined the potential contributions of CRF1 to altered synaptic plasticity in AD neuropathology and stress in the TgF344-AD rat model. In vivo electrophysiological recordings to assess long-term potentiation (LTP) in the perforant pathway to dentate gyrus synapses were performed in aged transgenic rats and wild-type (WT) controls (2-2.5 years). TgF344-AD rats had abnormal LTP measures of field excitatory post-synaptic potentials (fEPSP) and population spikes (PS). Treatment with Antalarmin did not alter LTP measures in TgF344-AD or WT rats. These observations indicate that LTP in TgF344-AD rats is reduced compared to WT rats and that acute treatment with a CRF1 antagonist did not rescue LTP deficits. Future research should further examine the mechanism of CRF1 in AD and implications of agonism or direct infusions of Antalarmin in vivo.},
}

Animals
*Long-Term Potentiation/drug effects/physiology
*Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors/metabolism
*Dentate Gyrus/drug effects/physiopathology
*Alzheimer Disease/physiopathology/drug therapy/pathology/genetics
*Pyrroles/pharmacology
*Pyrimidines/pharmacology
Disease Models, Animal
CRF Receptor, Type 1
Rats, Transgenic
Male
Rats
Rats, Inbred F344
Excitatory Postsynaptic Potentials/drug effects/physiology

@article {pmid42163277,
year = {2026},
author = {Lee, HJ and Seok, J and Kang, S and Oh, S and Hwang, JW and Kim, YJ and Seo, J and Hoe, HS},
title = {The insulin receptor inhibitor BMS-754807 alleviates neuroinflammation and Alzheimer's disease pathologies across human cellular and mouse models.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03855-7},
pmid = {42163277},
issn = {1742-2094},
support = {RS-2024-00357857//NRF/ ; RS-2024-00343370//KDRC/ ; H0501-25-1001//NIPA/ ; 20190058//Whanin Pharm Co., Ltd/ ; 26-BR-02-04, 26-BR-05-01, and 26-BR-06-01//KBRI funded by the Ministry of Science, ICT & Future Planning/ ; RS-2026-25492172//National Research Foundation of Korea/ ; },
abstract = {BACKGROUND: BMS-754807 is a dual inhibitor of insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) that is in phase II clinical trials for the treatment of HR-positive and HER2-negative breast cancer. Because IGF-1R signaling regulates inflammatory responses, pharmacological modulation of IGF-1R may have therapeutic potential for Alzheimer's disease (AD); however, the effects of BMS-754807 on neuroinflammatory responses/AD pathology and cognitive function have not been fully investigated.

METHODS: We examined whether BMS-754807 modulates neuroinflammation and AD pathologies in multiple in vivo animal models and in vitro human models. BMS-754807 (20 mg/kg, i.p.) was systemically administered in wild-type mice challenged with LPS, 5xFAD mice, and PS19 transgenic mice. In addition, human-induced pluripotent stem cell (hiPSC)-derived microglia challenged with LPS and AD hiPSC-derived neurons were treated with 2.5 µM BMS-754807. For all models, the effects of BMS-754807 treatment were analyzed by real-time PCR, immunofluorescence staining, western blotting, ELISA, and/or activity assays.

RESULTS: BMS-754807 treatment significantly decreased p-IGF-IR (on-target) levels, LPS-induced proinflammatory cytokine production, and reactive oxygen species levels; restored HO-1 expressions; and inhibited AKT/STAT3 signaling in BV2 microglial cells. Similarly, BMS-754807 treatment reduced LPS-evoked proinflammatory cytokine expressions in primary microglial cells and primary astrocytes. In addition, BMS-754807 administration mitigated LPS-stimulated gliosis, microglial/astrocyte-associated dynamics, STAT3/NF-κB phosphorylation, and potentially NLRP3 inflammasome in vitro and/or in WT mice. Moreover, BMS-754807 treatment suppressed LPS-mediated proinflammatory responses through IGF-1R and NLRP3 in BV2 microglial cells. In 5xFAD mice, BMS-754807 administration downregulated IGF-1R phosphorylation, microgliosis/astrogliosis-related dynamics, and AKT/P38/STAT3 pathway. Notably, BMS-754807 treatment also diminished LPS-induced proinflammatory cytokine levels and STAT3/NF-κB signaling in human microglial models. Furthermore, BMS-754807 treatment decreased Aβ40/Aβ42 levels in hiPSC-derived AD neurons, and increased short-term spatial memory and reduced Aβ plaque accumulation by decreasing β-secretase (BACE1) activity in 5xFAD mice. Finally, in hiPSC-derived AD neurons and PS19 mice, BMS-754807 treatment significantly attenuated tau hyperphosphorylation, CaMKIIα phosphorylation, and tau-mediated astroglial activation.

CONCLUSIONS: Taken together, our results suggest that BMS-754807 exerts anti-inflammatory and potential disease-modifying effects by attenuating LPS/Aβ/tau-evoked glial activation and reducing Aβ and tau pathologies in both human cellular and mouse models of neuroinflammation and AD. Furthermore, BMS-754807 administration improved specific domains of cognitive function in vivo. These findings support pharmacological inhibition of IGF-1R as a potential therapeutic approach for neuroinflammation-associated diseases including AD.},
}

@article {pmid42163384,
year = {2026},
author = {Hsu, JL and Huang, SY and Wu, HC and Lin, KJ and Huang, KL and Huang, CC and Kim, S and Hsiao, IT},
title = {A clinically feasible framework to estimate tau pathology and clinical-biological discordance in the Alzheimer's disease spectrum.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02083-8},
pmid = {42163384},
issn = {1758-9193},
support = {MOST 111-2314-B-182A-036-MY2, NSTC 112-2628-B-182-007-MY3, NSTC-113-2314-B-182-042-MY2, NSTC-114-2314-B-182-043, NSTC 114-2314-B-182A-061-MY3//National Science and Technology Council/ ; MOST 111-2314-B-182A-036-MY2, NSTC 112-2628-B-182-007-MY3, NSTC-113-2314-B-182-042-MY2, NSTC-114-2314-B-182-043, NSTC 114-2314-B-182A-061-MY3//National Science and Technology Council/ ; MOST 111-2314-B-182A-036-MY2, NSTC 112-2628-B-182-007-MY3, NSTC-113-2314-B-182-042-MY2, NSTC-114-2314-B-182-043, NSTC 114-2314-B-182A-061-MY3//National Science and Technology Council/ ; MOST 111-2314-B-182A-036-MY2, NSTC 112-2628-B-182-007-MY3, NSTC-113-2314-B-182-042-MY2, NSTC-114-2314-B-182-043, NSTC 114-2314-B-182A-061-MY3//National Science and Technology Council/ ; MOST 111-2314-B-182A-036-MY2, NSTC 112-2628-B-182-007-MY3, NSTC-113-2314-B-182-042-MY2, NSTC-114-2314-B-182-043, NSTC 114-2314-B-182A-061-MY3//National Science and Technology Council/ ; MOST 111-2314-B-182A-036-MY2, NSTC 112-2628-B-182-007-MY3, NSTC-113-2314-B-182-042-MY2, NSTC-114-2314-B-182-043, NSTC 114-2314-B-182A-061-MY3//National Science and Technology Council/ ; CORPG3P0281, CORPG3P0291, BMRP488//Chang Gung Memorial Hospital Research Fund/ ; CORPG3P0281, CORPG3P0291, BMRP488//Chang Gung Memorial Hospital Research Fund/ ; CORPG3P0281, CORPG3P0291, BMRP488//Chang Gung Memorial Hospital Research Fund/ ; CORPG3P0281, CORPG3P0291, BMRP488//Chang Gung Memorial Hospital Research Fund/ ; CORPG3P0281, CORPG3P0291, BMRP488//Chang Gung Memorial Hospital Research Fund/ ; CORPG3P0281, CORPG3P0291, BMRP488//Chang Gung Memorial Hospital Research Fund/ ; },
abstract = {BACKGROUND: Tau positron emission tomography (PET) is critical for biological staging and treatment stratification in Alzheimer's disease (AD), particularly in the era of anti-amyloid therapies where lower tau burden predicts greater clinical benefit. However, tau PET remains costly and inaccessible in many clinical settings. We aimed to develop and validate a clinically feasible framework to estimate global and regional tau burden using routinely available amyloid PET and clinical measures, aligned with the 2024 Alzheimer's Association (AA-2024) diagnostic framework, and to characterize clinical-biological discordance across the AD continuum.

METHODS: We conducted a cross-sectional study of 229 individuals spanning cognitively unimpaired, mild cognitive impairment, and dementia stages who underwent [[18]F]florbetapir amyloid PET, [[18]F]florzolotau tau PET, structural MRI, and cognitive assessment. Amyloid burden was quantified using the Centiloid (CL) scale (A+ defined as CL > 20). Tracer-specific tau thresholds for global and Braak-stage volumes were derived using two-component Gaussian mixture modeling. Logistic regression models incorporating CL, age, Mini-Mental State Examination (MMSE), and medial temporal lobe (MTL) volume were developed to classify high global tau burden and neocortical tau involvement. Among amyloid-positive individuals, biological staging was compared with clinical stage to assess discordance patterns.

RESULTS: Global and regional tau burden increased stepwise across clinical severity and amyloid strata. High global tau burden was uncommon in individuals with CL 21-60 (6.1%) but increased in CL 61-100 (22.6%) and > 100 (36.2%). A multivariable model integrating CL, age, MMSE, and relative MTL volume demonstrated good discrimination for high global tau burden (AUC = 0.87) and neocortical involvement (AUC = 0.84). Model robustness was confirmed by bootstrap resampling. Among amyloid-positive participants, 53.1% exhibited clinical-predominant AD, characterized by older age and higher cardiovascular risk despite relatively modest tau burden, indicating substantial clinical-biological discordance.

CONCLUSION: Routinely obtainable amyloid PET and clinical measures can approximate global and topographical tau burden with good accuracy and identify frequent clinical-biological discordance within the AD spectrum. This scalable framework provides a practical surrogate for tau PET in resource-limited settings and may support biological staging, therapeutic eligibility assessment, and precision treatment decision-making.},
}

@article {pmid42163678,
year = {2026},
author = {Jin, S and Liu, D and Ouyang, J},
title = {An Investigation of the Neurotoxic Mechanisms of Benzo[a]pyrene in Alzheimer's Disease Using an Integrated Approach of Network Toxicology and Machine Learning.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X447239260407111712},
pmid = {42163678},
issn = {1875-6190},
abstract = {INTRODUCTION: Benzo[a]pyrene (BaP) exposure is increasingly associated with the progression of Alzheimer's Disease (AD), yet the specific molecular links remain poorly understood. This study utilizes an integrated computational framework, combining network toxicology, machine learning, and molecular dynamics simulations, to identify core biomarkers and elucidate the potential pathological interplay between BaP and AD.

METHODS: We began our analysis by identifying the intersection of targets and then created a Protein-Protein Interaction (PPI) Network to identify hub genes. To ensure accuracy, we selected final core molecular targets from the intersection of three distinct types of machine learning algorithms. To validate diagnostic value, immune cell infiltration data analysis was performed using the GSE138260 dataset. Finally, we used molecular docking and 100 ns dynamics to assess how BaP interacts with the core molecular target.

RESULTS: We identified four proteins associated with BaP and AD: CASP3 (Caspase 3), HTT (Huntingtin), TH (Tyrosine Hydroxylase), and PARK7 (DJ-1). These proteins signal neuronal apoptosis and neuro-immune dysregulation due to their involvement in pathways associated with these processes. The Receiver Operating Characteristic (ROC) analysis demonstrated strong diagnostic properties for these targets. Molecular docking data also showed BaP as the main target, with TH binding with a value of -10.02 kcal/mol. The stability of this BaP-TH complex was further confirmed by 100 ns molecular dynamics simulations.

DISCUSSION: The research reveals TH's critical effect on BaP-induced neurotoxicity. We also identify the potential molecular mechanisms contributing to Alzheimer's disease pathology via environmental exposure.

CONCLUSION: This research identifies several significant molecular interactions between BaP and AD. One major molecular target for BaP interaction with AD is tyrosine hydroxylase (TH). Our findings here create an opportunity for the development of therapeutics for the treatment of AD cases caused by exposure to environmental toxins.},
}

@article {pmid42163745,
year = {2026},
author = {Abdalla, EA and Fayed, AM and Hussein, MA and Abdel-Aziz, A and Mohamed, ZN},
title = {Multi-Target Neuroprotection of Salvia officinalis Aqueous Extract in a Scopolamine-Induced Model of Alzheimer's Disease: Comparative Efficacy Versus Donepezil.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128429239260312074215},
pmid = {42163745},
issn = {1873-4286},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a complex, age-related, neurodegenerative disorder that involves cognitive deterioration, oxidative stress, and neuroinflammation. Symptomatic relief is limited with conventional treatments such as donepezil, sparking a significant interest in multi-target botanicals. We examined the neuroprotective effects of Salvia officinalis aqueous extract (SAGE) on a scopolamine-induced animal model of AD and the related molecular mechanisms regarding GABRA5α, GSK-3β, and pERK pathways.

METHODS: SAGE was characterized using phytochemical profiling and antioxidant assays. IC50 values were determined in vitro for inhibitor activity against GABRA5α and GSK-3β. In vivo experiments included assessment of behavior (Morris water maze), assays for oxidative stress and inflammation, gene expression studies by qPCR, and histopathology of hippocampal tissue. Efficacy versus donepezil was compared. Statistical significance was based on one-way ANOVA followed by Tukey's post-hoc test (p < 0.05) for robust comparisons between all treatment groups.

RESULTS: The SAGE had strong antioxidant abilities and was able to inhibit GABRA5α and GSK-3β in a target-specific way. SAGE treatment greatly enhanced spatial learning and memory, retained the redox equilibrium, decreased neuroinflammatory markers, and normalized AChE activity. Gene expression was found to modulate favourably for GABRA5α, GSK-3β and pERK. Histological findings confirmed neuronal preservation. In all parameters, SAGE was more effective than donepezil. The present findings demonstrated the therapeutic potential of SAGE's phenolics to mitigate oxidative cascades, including those suggested as contributing factors to AD pathology.

DISCUSSION: The superior multi-modal efficacy of SAGE over donepezil due to its phenolic-rich phytochemical profile and capacity to modulate oxidative, inflammatory, and neuronal pathways is demonstrated. This is encouraging, and additional studies should be conducted to investigate pharmacokinetics, mechanistic and clinical significance.

CONCLUSION: S. officinalis AE strongly protects the brain against scopolamine-induced AD-like neuropathology in a superior way over standard treatment via altered multi-targets. Its characteristics promote its further development as a natural therapeutic candidate for AD treatment. There are however constraints, such as nodescription of the pharmacokinetic profiling and no tau/Aβ quantification. Prospective studies with these endpoints and chronic dosing schedules should now address the issue of long-term effectiveness and safety.},
}

@article {pmid42164259,
year = {2026},
author = {Giorelli, M},
title = {Reframing Alzheimer's disease as a complex adaptive system: More than an amyloid beta-tau connection.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {},
pages = {e70256},
pmid = {42164259},
issn = {2352-8737},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia, but simple models focusing on amyloid beta and tau only partially explain its variability and limited success in treatment. Evidence from systems biology, neuroimmunology, connectomics, and computational modeling supports viewing AD as a complex adaptive system, a multiscale network in which genetic, molecular, cellular, vascular, and environmental factors interact in complex, non-linear ways over time. In this perspective, disease paths develop from feedback-driven instabilities that spread across different levels, while resilience and compensatory mechanisms influence individual outcomes. This new understanding has important implications: diagnostic approaches should shift from static lesion biomarkers to longitudinal, multimodal measures of network states; treatments should combine pharmacological, metabolic, vascular, inflammatory, cognitive, and neuromodulatory strategies; and adaptive, model-informed algorithms should customize the timing and dosage to each patient's unique dynamics. Recognizing the complexity enables earlier detection of critical tipping points, targeted reinforcement of resilience, and personalized intervention plans, shifting AD care from late-stage, single-target methods to precision network medicine.},
}

@article {pmid42164431,
year = {2026},
author = {Schuller, AJ and Hager, MR and Briggs, AM and Rocha, SM and Yanouri, OA and Smith, EJ and Hall, SE and Montrose, LB and Tjalkens, RB},
title = {Treadmill training induces sex-dependent changes in hippocampal epigenetic patterns and plaque-associated microglial morphology in aged TgF344 rats.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1805957},
pmid = {42164431},
issn = {1662-4548},
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder world-wide, characterized by progressive neuroinflammation, aberrant protein accumulation, and neuronal loss associated with cognitive decline. Although our understanding of the molecular mechanisms underlying AD pathogenesis has greatly increased in recent years, there remain limited treatment strategies and no cures for this disorder. Because of this, efforts have shifted toward identifying modifiable lifestyle factors which may decrease risk of onset or slow AD progression. One such approach which has shown promise in modulating the disease course is physical exercise. However, sex-specific effects of implementing such activity strategies in aged individuals after the onset of disease are less well studied. We sought to address this knowledge gap by characterizing hippocampal histopathology and DNA modification profiles of aged TgF344-AD rats following progressive treadmill-training. Reduced-representation bisulfite sequencing indicated 94 genes associated with differentially modified cytosines (DMCs) in exercised females (239 differentially modified regions, 54.6% hypermodified) and 87 DMC-associated genes in exercised males (216 differentially modified regions, 50.4% hypermodified) with unique functional enrichment for overrepresented pathways and protein interactions relevant to glial activation and synaptic plasticity. Using quantitative high-throughput slide scanning fluorescence microscopy we additionally examined this brain region for AD-relevant changes including neuronal and microglial density, microglial morphology, and accumulation of pathologic protein. This analysis revealed female-specific reductions in NeuN[+] and Iba1[+] cells in treadmill-trained animals, as well as sex- and exercise-dependent changes in plaque-associated microglial reactivity state. Together, these findings reveal that age of onset, biologic sex, and duration of physical exertion may be important factors in modulating the pathologic progression of AD.},
}

@article {pmid41975292,
year = {2026},
author = {Esmaeili, H and Mahdavi-Fikjvar, E and Poureshaghi, F and Moridi Farimani, M and Sonboli, A and Dastres, E and Behboudi, H and Mirjalili, MH},
title = {Variation in phytochemical profiles and anti-cholinesterase activity across wild Iranian populations of Leucojum aestivum L.: a conservation perspective.},
journal = {BMC plant biology},
volume = {26},
number = {1},
pages = {},
pmid = {41975292},
issn = {1471-2229},
abstract = {BACKGROUND: Leucojum aestivum L. (Amaryllidaceae) is a perennial bulbous species of high pharmaceutical importance, primarily recognized as a natural source of the alkaloid galantamine for Alzheimer’s disease treatment. Iranian L. aestivum populations (LAPs) may contain unique alkaloids with strong acetylcholinesterase (AChE) inhibitory effects, making them a conservation priority. To investigate phytochemical diversity and bioactivity, eight natural populations including LAP1 (Chahar Deh, Astaneh Ashrafieh); LAP2 (Baz Kia Gurab, Lahijan); LAP3 (Sangar); LAP4 (Chomesghal, Ziabar); LAP5 (Pinchah, Astaneh Ashrafieh); LAP6 (Chaboksar); LAP7 (Valiseh, Rudsar); and LAP8 (Vali Abad, Tonkabon) were sampled during the flowering stage. Galantamine, lycorine, total phenolic content (TPC), total flavonoid content (TFC), antioxidant capacity (FRAP and DPPH), and AChE inhibitory activity were quantified in bulbs and leaves.

RESULTS: The highest AChE inhibition was recorded in bulbs of LAP6 (IC50: 95.57 µg/ml) and LAP7 (IC50: 102.38 µg/ml), corresponding to elevated galantamine levels (20.31 and 24.92 mg/g dry extract, respectively), which showed a strong positive correlation (r = 0.880, p < 0.01). In contrast, LAP8 contained no detectable galantamine in bulbs but exhibited exceptionally high leaf lycorine content (107.91 mg galanthamine equivalent/g dry extract) and antioxidant capacity (FRAP: 90.71 µmol Fe²⁺/g DW; DPPH, IC₅₀: 95.10 µg/ml), alongside moderate AChE inhibition (IC50: 150.80 µg/ml in bulbs, 231.63 µg/ml in leaves). Leaf TPC (8.57–13.39 mg GAE/g DW) consistently exceeded bulb TPC (0.18–7.59 mg GAE/g DW). Cluster analysis grouped populations into three distinct classes: balanced alkaloid levels and antioxidant power (LAP1, LAP5, LAP6), lower alkaloid levels (LAP2, LAP3, LAP4), and high phenolic content and antioxidant power with relatively elevated alkaloid levels (LAP7, LAP8).

CONCLUSIONS: These findings demonstrated a strong linkage between alkaloid composition and bioactivity, highlighting the pharmaceutical potential of specific chemotypes and emphasizing the necessity of in situ conservation and ex situ cultivation for sustainable utilization and drug development targeting cholinesterase inhibition and antioxidant activity.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12870-026-08717-1.},
}

@article {pmid42151697,
year = {2026},
author = {Visentini, AE and Reichert, KP and Schetinger, MRC and Bottari, NB and Miron, VV and Castro, MFV and da Silveira, MV and Assmann, CE and Schirmann, AA and Morsch, VMM},
title = {Resveratrol as a potential natural compound to ameliorate cognitive impairment in aluminum-exposed mice: impacts on behavior, purinergic system, and brain inflammation.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42151697},
issn = {1573-7365},
abstract = {UNLABELLED: Aluminum (Al[3+]) accumulates in the brain and has been linked to neurodegeneration. When combined with citrate, its absorption increase, raising the risk of neurodegenerative disorders such as Alzheimer’s disease. Resveratrol (RSV), a polyphenol with anti-inflammatory, antioxidant, and neuroprotective properties, has been associated with aging prevention by reducing oxidative stress. This in vivo study aimed to determine whether RSV could protect male Swiss mice from Al[3+]-induced cognitive impairment, alterations in purinergic signaling, and brain inflammation. The study was conducted using 60 animals treated with aluminum chloride (AlCl3 50 mg/Kg, gavage), citrate (AlCl3 50 mg/Kg + CIT 100 mg/Kg, gavage), and resveratrol (AlCl3 50 mg/Kg + RSV 100 mg/Kg, gavage), along with their respective Controls, for 30 days every 48 h. Behavioral assessments included the open field test, object recognition test, and Y-maze test to evaluate cognitive performance. Enzymatic activity of purinergic pathways and levels of receptors and inflammation-related molecules were also analyzed. AlCl3 and AlCl3 + CIT induced an inflammatory response in mice, as evidenced by the modulation of purinergic system enzymes associated with inflammation. Al[3+] intoxication also triggered behavior alterations, which was modulated by CIT and alleviated by RSV treatment. Western blot findings revealed that AlCl3 and AlCl3 + CIT altered protein levels of purinergic receptors (A1R, A2AR, and P2 × 7R), the inflammasome protein NLRP3, the pro-inflammatory cytokine IL-1β, and the neurotrophic factor BDNF. RSV counteracted the toxic effects of Al[3+], providing neuroprotection against its toxicity and presenting itself as a potential therapeutic candidate for cognitive deficits.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11011-026-01859-z.},
}

@article {pmid42152645,
year = {2026},
author = {Kishor, K and Arora, A and Yashika, and Yadav, S and Singh, A},
title = {Extracellular Vesicles in Alzheimer's Disease: Mechanisms, Immunotherapy Links, and Clinical Translation.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128464813260512100753},
pmid = {42152645},
issn = {1873-4286},
abstract = {Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by synaptic dysfunction, neuroinflammation, and cognitive impairment. Although amyloid-β and tau continue to serve as core biomarkers and therapeutic targets, the clinical efficacy of recent biologic agents targeting amyloid has led to a new paradigm in AD treatment. Nevertheless, emerging data show that lipid metabolism is an important and well-established aspect of AD pathophysiology rather than a new theory. Lipid processing in microglia, astrocytes, and neurons is disrupted, leading to chronic inflammation, impaired amyloid clearance, mitochondrial dysfunction, and synaptic dysfunction. This review critically analyzes how lipid accumulation and lipid droplet biology contribute to Alzheimer's disease using cellular, animal, and human studies. Special focus is placed on enzymatic regulators such as DGAT2, cholesterol transport, and neuron-glia metabolic linkages. This review synthesizes existing mechanistic and translational data to emphasize lipid dysregulation as a complementary therapeutic target and potential biomarker axis that may improve current amyloid- and taudirected therapeutic strategies.},
}

@article {pmid42152660,
year = {2026},
author = {Younas, S and Badshah, I and Akbar, K and Al-Otaibi, JS and Khan, H},
title = {3-(2,4-Dimethylbenzylidene)-6-chloroindolin-2-one Alleviates Memory Impairment in D-Galactose-induced Alzheimer Like Pathology in a Mouse Model.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X434400260421062719},
pmid = {42152660},
issn = {1875-6190},
abstract = {INTRODUCTION: Oxidative stress and neuroinflammation are the main contributors to Alzheimer's disease (AD). The current study evaluated the neuroprotective efficacy of 3-(2,4- dimethylbenzylidene)-6-chloroindolin-2-one (DMO) against D-Galactose (GAL)-induced neuroinflammation, oxidative stress, and memory impairment in mice.

METHODS: Swiss Male albino mice weighing (25-30 g) were assigned to five experimental groups (n=6) (i) Normal group (received normal saline 0.9%) (ii) Control group (received GAL 100 mg/kg i.p) (iii) Standard group (received Donepezil 5 mg/kg + GAL 100 mg/kg i.p) (iv) Treatment group 1 (received DMO 5 mg/kg + GAL 100 mg/kg i.p) and Treatment group 2 (received DMO 10 mg/kg + GAL 100 mg/kg i.p) once daily for 8 weeks. After treatment, the mice were subjected to behavioral analysis, followed by sacrifice for further analysis.

RESULTS: DMO alleviated GAL-induced cognitive impairment as shown by the Morris water maze test (MWM), Y-maze, elevated plus maze (EPM), and open field (OF) test. Brain tissue histology showed reversal of distorted neuronal structures and decreased pyknosis upon DMO treatment. DMO also decreased the levels of Glutathione-S-Transferase (GST), reduced Glutathione (GSH), and catalase (CAT), concomitant with increased lipid peroxidase (LPO). Furthermore, levels of TNF-α and NF- ҡB, were significantly reduced in the DMO treatment groups as quantified by ELISA. In addition, Reverse transcription polymerase chain reaction (RT-PCR) showed a substantial decrease in the expression of β-amyloid and Tau protein.

DISCUSSION: The results showed that DMO inhibits D-gal induced oxidative stress, neuroinflammation and consequently alleviates memory impairment.

CONCLUSION: Our novel findings suggest that DMO could be a promising therapeutic modality for the treatment of brain aging-associated disorders.},
}

@article {pmid42152670,
year = {2026},
author = {Bjørklund, G and Izmailovich, M and Glushkova, N and Semenova, Y},
title = {Vitamin E in Alzheimer's Disease: A Perspective on Antioxidant Therapy.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673386940251024110821},
pmid = {42152670},
issn = {1875-533X},
abstract = {This study explores the relationship between vitamin E and Alzheimer's disease (AD), a neurodegenerative disorder characterized by cognitive decline, memory loss, and language impairment. Vitamin E is a fat-soluble antioxidant crucial in protecting cells from oxidative damage. The biochemistry and bioavailability of vitamin E are discussed, including its absorption, transport, and storage in the body. The section on interactions between vitamin E and other nutrients and herbals highlights how combining vitamin E supplements with other supplements or medications can affect its absorption, metabolism, and effectiveness. This study also discusses the potential therapeutic effects of vitamin E on AD, including its ability to reduce oxidative stress and inflammation, which are thought to play a role in the pathophysiology of AD. It explores the synergistic effects of vitamin E with pharmaceuticals and potential side effects, and covers the use of vitamin E in combination with other drugs for AD treatment, such as cholinesterase inhibitors and memantine, as well as the possible adverse effects of vitamin E supplementation. Overall, this study highlights the importance of vitamin E in preventing and managing AD and underscores the need for further research in this area.},
}

@article {pmid42152699,
year = {2026},
author = {Oba, GMJ and Sahu, R and Shah, K and Singh, AP},
title = {Interesting Potential Derivatives Based on the Coumarin Scaffold for the Treatment of Alzheimer's Disease.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575449515260428094401},
pmid = {42152699},
issn = {1875-5607},
abstract = {As the most common and deadly age-related neurodegenerative disease, Alzheimer's Disease (AD) affects the vast majority of elderly individuals. As such, new drugs are being produced, and their safety is still being assessed. Coumarin-based medications are among the most important pharmacophores in both natural and synthetic medicinal compounds. Targeting several essential receptors or enzymes, this six-membered aromatic heterocycle, linked by two oxygen atoms, has numerous therapeutic applications in research and offers many opportunities for future improvements in anti-Alzheimer's drugs. Several coumarin compounds have been shown to inhibit not just enzymes and receptors but also a wide range of additional targets involved in the battle against AD. The expansion of new derivatives based on coumarins in conjunction with other moieties for the treatment of AD is the current focus of research. In order to help scientists design effective drugs with the right pharmacological activity, this study sheds light on the current therapeutic expansion of coumarin-based derivatives as well as their synthesis methods.},
}

@article {pmid42152706,
year = {2026},
author = {Karayat, M and Kaushik, N and Paliwal, D},
title = {Scopoletin as a Potential Therapeutic Agent for Neurodegenerative Disorders: Mechanisms and Perspectives.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266399675251201111538},
pmid = {42152706},
issn = {1873-4294},
abstract = {Neurodegenerative diseases, such as Alzheimer's and Parkinson's, continue to pose significant challenges due to their complex aetiology and limited treatment options. Scopoletin, a naturally occurring coumarin found in a variety of medicinal plants, is being explored as a potential therapeutic agent because of its broad pharmacological profile. This review investigates scopoletin's neuroprotective potential, with particular emphasis on its antioxidant, anti-apoptotic, and cholinergic-regulating properties. It also highlights its ability to reduce oxidative stress, modulate neurotransmitter balance, and prevent protein aggregation, which are key pathological features of neurodegeneration. Despite promising preclinical findings, further research is required to establish its efficacy, optimise its bioavailability, and evaluate its safety in clinical settings. Overall, scopoletin demonstrates considerable potential as a neuroprotective compound, offering new avenues for the development of innovative therapeutics for neurodegenerative disorders. This comprehensive review aims to provide a foundation for future research and the advancement of scopoletin as a promising agent against neurodegeneration.},
}

@article {pmid42157023,
year = {2026},
author = {Rybicki-Kler, CI and Brooks, IAW and Jedrasiak-Cape, I and Deng, T and Avila, C and Brouns, E and Lekander, A and Ahmed, OJ},
title = {Reciprocal molecular and cellular cholinergic working memory impairments in Alzheimer's disease model mice.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71490},
doi = {10.1002/alz.71490},
pmid = {42157023},
issn = {1552-5279},
support = {R01MH129282/MH/NIMH NIH HHS/United States ; R34NS127101/NS/NINDS NIH HHS/United States ; P50NS123067/NS/NINDS NIH HHS/United States ; T32NS007222/NS/NINDS NIH HHS/United States ; T32NS076401/NS/NINDS NIH HHS/United States ; P30AG072931/AG/NIA NIH HHS/United States ; F31AG087629/AG/NIA NIH HHS/United States ; AARG-NTF-21-846572/ALZ/Alzheimer's Association/United States ; T32DC000011/DC/NIDCD NIH HHS/United States ; G102865/321033//Berger Endowment/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/pathology ; Disease Models, Animal ; Mice ; *Memory, Short-Term/physiology ; Mice, Transgenic ; *Cholinergic Neurons/metabolism ; Receptor, Muscarinic M1/metabolism/genetics ; Humans ; Cerebral Cortex/metabolism ; Acetylcholine/metabolism ; *Memory Disorders ; },
abstract = {INTRODUCTION: The degeneration of basal forebrain cholinergic neurons is a key pathophysiological feature of Alzheimer's disease (AD). These cholinergic neurons target cortical neurons including those in the granular retrosplenial cortex (RSG) to facilitate essential cognitive functions. At the cellular level, acetylcholine supports working memory by inducing persistent firing that outlasts the stimulus, but how such cholinergic-induced persistent firing is altered in AD remains unknown.

METHODS: Using multiscale molecular and cellular analyses, we investigated neuron type-specific transcriptomic and physiological impairments of cholinergic persistent signaling in the RSG of 5xFAD mice.

RESULTS: Cholinergic inputs to RSG were reduced in 5xFAD mice. Expression of the Chrm1 gene encoding M1 muscarinic receptors was also reduced in RSG neurons, coupled with impaired cellular persistent firing.

DISCUSSION: The loss of M1 receptors suggests that allosteric M1 modulators being considered for treatment of AD symptoms may not be as effective on key cell types, necessitating further multiscale investigation.},
}

Animals
*Alzheimer Disease/metabolism/genetics/pathology
Disease Models, Animal
Mice
*Memory, Short-Term/physiology
Mice, Transgenic
*Cholinergic Neurons/metabolism
Receptor, Muscarinic M1/metabolism/genetics
Humans
Cerebral Cortex/metabolism
Acetylcholine/metabolism
*Memory Disorders

@article {pmid42157276,
year = {2026},
author = {Krick, KE and Chalk, JL and Lykins, JT and Wang, HP and Ferguson, CA and Shahid, SS and Weekman, EM and Wilcock, DM},
title = {TNF inhibition differentially impacts regional Abeta immunotherapy efficacy in the humanized hAb[SAA] mouse model.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02084-7},
pmid = {42157276},
issn = {1758-9193},
support = {1RF1NS130834//Foundation for the National Institutes of Health/ ; },
abstract = {BACKGROUND: The FDA approval of amyloid beta (Aβ) targeting immunotherapies offered the first opportunity to clinically modify Alzheimer's disease progression and give patients back precious months in the course of disease progression. The administration of these therapeutics has uncovered a common side effect called Amyloid Related Imaging Abnormalities (ARIA). While often asymptomatic, these adverse events have potential to escalate, and their commonality has encouraged further studies to mitigate their incidence. Increases in immune activation are important in immunotherapy action, though heightened release of cytokines have also been shown in ARIA development. TNF has been shown in early studies to increase with immunotherapy administration and subsequent ARIA development and TNF itself has been implicated in blood brain barrier dysfunction which could contribute to hemorrhagic ARIA (ARIA-H) development.

METHODS: This study assessed hemorrhage outcomes in an aged mouse model using MRI and Prussian blue histology, explored transcriptomic and protein changes with NanoString nCounter and Meso Scale Discovery, and we performed immunohistochemical stains for microglia/macrophages, astrocytes, and pericyte changes.

RESULTS: In this study, we established ARIA-H pathology in a humanized mouse model (hAβ[SAA]) via chronic Aβ immunotherapy administration. We saw significant hemorrhagic lesions in our model, despite low levels of cortical cerebral amyloid angiopathy (CAA) suggesting a role for CAA as a risk factor for ARIA but potentially not its driver. We also explored the role of TNF in ARIA progression by inhibiting soluble TNF alongside immunotherapy administration as a potential combination therapeutic to address ARIA. With TNF inhibition, we saw a reduction of hemorrhages in the hippocampus, but not in the cortex, suggesting a regional effect. Further, we saw additional regional differences between the cortex and hippocampus with TNF inhibition including macrophage activation markers and amyloid levels, suggesting a differential role for TNF signaling in these areas and a potential heterogeneity of cellular responses in each region.

CONCLUSION: We induced ARIA without significant cortical CAA pathology and identified regional differences with TNF inhibition including a potential benefit of treatment in the hippocampus and possible detriment to pathology in the cortex.},
}

@article {pmid42157624,
year = {2026},
author = {Granberg, T and Blystad, I and Fällmar, D and Savitcheva, I and van Westen, D and Westman, E},
title = {[Brain imaging in cognitive disorders - from diagnosis to treatment and monitoring].},
journal = {Lakartidningen},
volume = {123},
number = {},
pages = {},
pmid = {42157624},
issn = {1652-7518},
mesh = {Humans ; Magnetic Resonance Imaging ; *Neuroimaging/methods ; Tomography, X-Ray Computed ; *Cognition Disorders/diagnostic imaging/therapy/diagnosis ; *Brain/diagnostic imaging/pathology ; Alzheimer Disease/diagnostic imaging/therapy ; Positron-Emission Tomography ; },
abstract = {Brain imaging is essential in the diagnostic workup of cognitive disorders. Computed tomography (CT) is usually the first-line method due to accessibility and patient comfort, whereas magnetic resonance imaging (MRI) offers higher diagnostic precision and is required before anti-amyloid therapy. MRI adds value by detecting microvascular pathology, enabling volumetric analysis, and ensuring safe monitoring of amyloid-related imaging abnormalities (ARIA). National Swedish MRI protocols and structured reporting templates support harmonized diagnostics and follow-up. Nuclear medicine methods are useful for complex cases to assess glucose metabolism, amyloid burden or dopamine transport function. With emerging treatment options for Alzheimer's disease, standardized imaging and close collaboration across specialties are essential for upscaling diagnostic routines and for safe and efficient care.},
}

Humans
Magnetic Resonance Imaging
*Neuroimaging/methods
Tomography, X-Ray Computed
*Cognition Disorders/diagnostic imaging/therapy/diagnosis
*Brain/diagnostic imaging/pathology
Alzheimer Disease/diagnostic imaging/therapy
Positron-Emission Tomography

@article {pmid42157845,
year = {2026},
author = {Bouton, J and Bretteville, A and Tresadern, G and Shaffer, P and Austin, N and Buijnsters, P and Cedervall, EP and Darville, N and Fonteyn, I and Leenaerts, J and Lamenca, CM and Mertens, L and Peeters, D and Velter, AI and Roosbroeck, YV and Ebneth, A and Bartolomé, JM and Trabanco, AA and Oehlrich, D},
title = {Discovery of 5‑Azaindole Inhibitors of O‑GlcNAcase for the Treatment of Alzheimer's Disease and Related Tauopathies.},
journal = {ACS medicinal chemistry letters},
volume = {17},
number = {5},
pages = {1096-1105},
pmid = {42157845},
issn = {1948-5875},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by extracellular amyloid-β plaque accumulation and intracellular tau neurofibrillary tangles, with tau pathology correlating more closely with cognitive decline. Modulation of tau phosphorylation through the regulation of O-GlcNAcylation, a post-translational modification controlled by O-GlcNAcase (OGA), represents a promising therapeutic strategy. In this study, we report the optimization of a pyrimidine hit identified by high-throughput screening, leading to the discovery and optimization of a novel series of 5-azaindole-based OGA inhibitors. From this series, compound 24 was identified as an in vivo tool candidate that demonstrated a favorable pharmacokinetic profile and measurable brain exposure. Pharmacodynamic studies in murine models demonstrated that compound 24 induced a significant and transient elevation of brain O-GlcNAcylation levels, confirming the in vivo target engagement. These findings underscore the potential of 5-azaindole-based OGA inhibitors as a novel validated chemotype for modulation of O-GlcNAcylation.},
}

@article {pmid42157881,
year = {2026},
author = {Jabbari, S and Zakaria, ZA and de Menezes, IRA and Mohammadi, S},
title = {Rhamnazin attenuates Amyloid β-Peptide (1-42) induced spatial memory impairments by modulation of BDNF-ERK signaling pathway.},
journal = {3 Biotech},
volume = {16},
number = {6},
pages = {200},
pmid = {42157881},
issn = {2190-572X},
abstract = {Rhamnazin (Rham), a natural flavonoid, possesses various medicinal benefits including anti-inflammatory, antioxidant, antiangiogenic, and antibacterial activities. Additionally, Rham showed neuroprotective effects when assessed using the chronic stress-induced cognitive impairment assay. In this intriguing investigation, researchers delved into the working memory and spatial reference memory of Rham, utilizing a rat model of Alzheimer's disease (AD) induced by amyloid β1-42 (Aβ1-42). Administering Aβ1-42 directly into the ventricles led to notable cognitive impairments in behavioral assessments of rats with AD. However, chronic treatment of Rham (30, 60, and 120 mg/kg) once per day during five consecutive days improved the cognitive functions of AD-induced rats in a dose-dependent manner which was not observed following the acute Rham treatment. Concurrently, Rham administration also increased the levels of BDNF and phosphorylated ERK in the hippocampus. Moreover, the cognitive boost triggered by Rham was replicated through the overproduction of BDNF in the hippocampus. However, this effect was thwarted by either the bilateral delivery of lentiviruses expressing BDNF shRNA into the hippocampus or by a targeted injection of an ERK inhibitor. In conclusion, chronic treatment with Rham improves the cognitive deficits in AD-induced rats possibly via the upregulation of BDNF/ERK signaling pathway in hippocampus.},
}

@article {pmid42157911,
year = {2025},
author = {Waqar, Z and Sethi, P and Jain, D and Singh, K and Alsaidan, OA and Alzarea, SI and Gupta, JK and Saxena, S and Sharma, MC},
title = {Precision Medicine in Neurodegenerative Diseases: Genomic Approaches to Target Amyloid-β, Tau, and Alpha-Synuclein Pathways.},
journal = {Current genomics},
volume = {26},
number = {6},
pages = {469-494},
pmid = {42157911},
issn = {1389-2029},
abstract = {Neurodegenerative diseases, including Alzheimer's and Parkinson's disease, are characterized by the pathological aggregation of proteins such as amyloid-β, tau, and alpha-synuclein. These hallmark proteins play central roles in disease progression and represent promising targets for therapeutic intervention. Advances in precision medicine, driven by genomic technologies such as CRISPR-Cas systems, RNA-based therapies, and high-throughput sequencing, have enabled the development of tailored strategies to modulate these pathological pathways. This review examines the integration of genomic approaches in targeting amyloid-β, tau, and alpha-synuclein, emphasizing their potential to mitigate disease progression and improve patient outcomes. We highlight current progress in preclinical and clinical studies, discuss challenges associated with translating these therapies into clinical practice, and explore future directions for achieving therapeutic precision in neurodegenerative disorders. By examining the interplay of genetic, molecular, and therapeutic innovations, this review underscores the transformative potential of genomic medicine in addressing the unmet needs of neurodegenerative disease treatment.},
}

@article {pmid42157943,
year = {2026},
author = {Li, R and Yao, J and Peng, W and Zheng, L and Wu, X and Shui, X and Zheng, X and Tian, W and Wang, L and Zhou, Y and Ruan, X and Pan, X and Zhang, T and Liu, Y and Lee, TH and Chen, D},
title = {A Novel PROTAC Confers a Dual Benefit Against Amyloid and Tau Pathology in Alzheimer's Disease via DAPK1 Degradation.},
journal = {International journal of biological sciences},
volume = {22},
number = {9},
pages = {4724-4746},
pmid = {42157943},
issn = {1449-2288},
mesh = {*Death-Associated Protein Kinases/metabolism/genetics ; Animals ; *Alzheimer Disease/metabolism/drug therapy ; Mice ; Female ; Humans ; *tau Proteins/metabolism ; *Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; Proteolysis ; Phosphorylation ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that is caused by multiple factors, characterized by a progressive decline in cognitive ability, extracellular amyloid-β (Aβ) plaques, and intracellular neurofibrillary tangles composed of hyperphosphorylated tau. Current treatment strategies can provide only symptomatic treatment or limited efficacy, highlighting the need to intervene in the upstream regulatory factors that drive both amyloid and tau pathologies. Death-associated protein kinase 1 (DAPK1) is a key driver upstream of both amyloid precursor protein processing and tau phosphorylation, simultaneously promoting amyloidogenesis and tau-mediated pathology in AD. In this study, we developed CP1, a bifunctional proteolysis-targeting chimera (PROTAC), to recruit E3 ubiquitin ligase to DAPK1, thereby inducing the ubiquitination and proteasomal degradation of DAPK1. CP1 efficiently eliminated the DAPK1 protein in primary cortical neurons without affecting its mRNA level, resulting in reduced Aβ generation and tau hyperphosphorylation. In vivo, upon systemic administration, CP1 effectively crossed the blood-brain barrier, degraded DAPK1, and consequently reduced the Aβ plaque burden and mitigated neuroinflammation in female 5xFAD mice. In a AAV-hTau-P301L tauopathy model, CP1 treatment suppressed tau hyperphosphorylation, preserved NeuN- and MAP2-positive neurons, attenuated astrocytic and microglial activation, and ultimately restored learning and memory abilities in both male and female mice. In summary, these findings demonstrate that degrading DAPK1 via a PROTAC strategy simultaneously mitigates both amyloid and tau pathology, indicating that CP1 is an effective candidate for disease-modifying therapy.},
}

*Death-Associated Protein Kinases/metabolism/genetics
Animals
*Alzheimer Disease/metabolism/drug therapy
Mice
Female
Humans
*tau Proteins/metabolism
*Amyloid beta-Peptides/metabolism
Mice, Transgenic
Proteolysis
Phosphorylation

@article {pmid42158156,
year = {2026},
author = {Li, R and Chen, Z and Jiang, Y and Yan, S and He, J and Yan, J and Zong, G and Yi, Z and Ren, X and Jia, B},
title = {Electroacupuncture for treating the cognitive symptoms of Alzheimer's disease: a randomized controlled trial.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1834514},
pmid = {42158156},
issn = {1664-0640},
abstract = {INTRODUCTION: The long-term efficacy of electroacupuncture (EA) in treating cognitive symptoms of Alzheimer's disease (AD) remains unclear, and its time-dependent relationship requires further investigation.

METHODS: Sixty-six patients were allocated to the EA or sham EA group, with stimulation for 20 minutes, for a 24-week treatment period, and were followed-up at 4 weeks. The primary outcome was the mean change in the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) score. Activities of daily living and behavioral and psychological symptoms were also assessed.

RESULTS: After 24 weeks of intervention, patients demonstrated significant improvements in ADAS-Cog scores, with sustained benefits observed during the 4-week follow-up period. In addition, improvements were observed in activities of daily living and behavioral and psychological symptoms.

DISCUSSION: The use of EA as a promising nonpharmacological intervention for AD.

CLINICAL TRIAL REGISTRATION: https://www.chictr.org.cn/showproj.html?proj=151275, identifier (ChiCTR2200056329).},
}

@article {pmid41943055,
year = {2026},
author = {Di Caro, V and Cho, E and Thiel, J and Lizama, BN and Koel-Simmelink, MJA and Pandey, K and Duong, D and Seyfried, NT and Grundman, M and Teunissen, CE and Zetterberg, H and Blennow, K and Caggiano, AO and Hamby, ME},
title = {Impact of zervimesine on the neuroinflammatory biomarker GFAP and related proteomic molecular correlates in plasma of participants from a phase 2 clinical trial in Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {41943055},
issn = {1758-9193},
support = {1R01AG058660/AG/NIA NIH HHS/United States ; 1R01AG058660/AG/NIA NIH HHS/United States ; 1R01AG058660/AG/NIA NIH HHS/United States ; 1R01AG058660/AG/NIA NIH HHS/United States ; 1R01AG058660/AG/NIA NIH HHS/United States ; 1R01AG058660/AG/NIA NIH HHS/United States ; 1R01AG058660/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Zervimesine (CT1812) is an investigational brain-penetrant small molecule modulator of the sigma-2 receptor (S2R/TMEM97), currently in clinical development for the treatment of Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) that selectively prevents and displaces the binding of amyloid beta (Aβ) and α-synuclein oligomers from neuronal synapses. Given the mechanism of action, it was hypothesized that zervimesine might be more effective in patients with lower levels of AD pathology. Indeed, in the SHINE trial, a completed Phase 2, randomized, double-blind, clinical trial conducted in participants with AD, a robust, 95%, slowing of cognitive decline, as assessed via ADAS-Cog11, was observed in a pre-specified subgroup of participants with lesser AD pathology (i.e., low p-tau217 subgroup) compared to a 38% slowing in the overall modified intent-to-treat (mITT)) population.

METHODS: In SHINE, exploratory plasma biomarkers were assessed using both a targeted and an unbiased, proteomics discovery approach in plasma from participants at baseline and end of study. Treatment effects of zervimesine relative to placebo were assessed in both the mITT population and in a low p-tau217 subgroup, who entered the study with lower (< 1pg/ml) plasma p-tau217 concentrations. Plasma biomarkers Aβ40, Aβ42, GFAP, NfL and BD-tau were assessed using clinically validated targeted assays, along with untargeted TMT-mass spectrometry (MS)-based discovery proteomics followed by bioinformatic, pathway and correlation analyses.

RESULTS: Collectively, plasma biomarker findings in the low p-tau217 subgroup were more robust than in the mITT population. Levels of GFAP were significantly decreased and NfL, Aβ42 and Aβ40 levels trended towards a decrease with zervimesine compared to placebo. Proteomics analyses identified candidate pharmacodynamic biomarkers of zervimesine, and gene ontology and pathway analyses pointed to an impact on amyloid biology, trafficking, lipid metabolism, and immune response. Bioinformatics and correlation analyses with GFAP identified biomarkers that may reflect pathway engagement of S2R and/or decreased neuroinflammation.

CONCLUSIONS: Exploratory plasma biomarker findings align with the degree of clinical benefit in SHINE mITT and low p-tau217 populations, and support future trial enrichment with patients with lower levels of pathology as defined by lower baseline plasma levels of p-tau217.

TRIAL REGISTRATION: July 20th, 2018 ClinicalTrials.gov Identifier NCT03507790 https://clinicaltrials.gov/study/NCT03507790.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-02025-4.},
}

@article {pmid42148948,
year = {2026},
author = {Li, X and Xiao, Y and Liu, F},
title = {Stevioside extends the healthspan and improves Alzheimer's disease and increases oxidative stress resistance via the mitochondrial unfolded protein response.},
journal = {Food & function},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6fo00251j},
pmid = {42148948},
issn = {2042-650X},
abstract = {Increased evidence suggests that moderate activation of the mitochondrial unfolded protein response (UPR[mt]) can delay aging and ameliorate neurodegenerative pathologies. Stevioside (Ste), a natural zero-calorie sweetener extracted from Stevia rebaudiana, has gained global acceptance as a sugar substitute in the food industry. Accumulated studies indicate that stevioside exhibits a wide spectrum of biological effects, including anti-hyperglycemic, anti-hypertensive, anti-inflammatory, and antimicrobial activities. However, its potential roles in aging and neurodegenerative diseases remain poorly understood. In this study, the lifespan of Caenorhabditis elegans was found to be prolonged upon exposure to (1, 10, and 100 μM) stevioside in a dose-dependent manner. Furthermore, we found that stevioside extended the lifespan and healthspan in C. elegans via activation of the ATFS-1-mediated UPR[mt] pathway. Intriguingly, the amelioration of Alzheimer's disease-related phenotypes by stevioside was also mediated through the ATFS-1 pathway. Additionally, we found that stevioside increased the resistance of oxidative stress and reduced ROS levels and upregulated superoxide dismutase (SOD) activity in C. elegans via the ATFS-1 pathway. These results demonstrated that both the anti-aging and neuroprotective effects of stevioside in C. elegans required a functional ATFS-1-dependent mitochondrial unfolded protein response. Collectively, our work highlighted that stevioside might be a viable candidate for the prevention and treatment of aging and age-related diseases.},
}

@article {pmid42149381,
year = {2026},
author = {Han, L and Xiong, X and Fan, M and Zhang, L and Gao, S and Li, R and Wang, X and Xiao, X and Huang, C and Yang, J},
title = {Early-Life Psychological Stress Impairs Spatial Learning and Memory in Rats by Altering the Hippocampal Proteome.},
journal = {Behavior genetics},
volume = {},
number = {},
pages = {},
pmid = {42149381},
issn = {1573-3297},
support = {82201342//National Natural Science Foundation of China/ ; xzy022023022//Xi 'an Jiaotong University Basic Research Student Project/ ; 2022PT-07//the Scientific Research and Sharing Platform Construction Project of Shaanxi Province/ ; },
abstract = {Early-life stress has been linked to anxiety, pessimism, and cognitive decline, all of which can have detrimental effects on individuals. One critical structure impacted by early-life stress is the hippocampus, which plays a vital role in regulating learning and memory functions. This study aims to elucidate the molecular mechanisms through which early-life psychological stress (ELPS) affects the learning and memory capabilities of the hippocampus in rats. In this study, ELPS model was applied on juvenile rats for 14 days. To evaluate the spatial learning and memory abilities of rats, the Morris Water Maze (MWM) test was adopted in this study. This study employed two-dimensional gel electrophoresis (2DE) and ultrahigh-performance liquid chromatographic-electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-Q-TOF-MS) techniques to reveal the proteomic map of the rat hippocampus. Subsequently, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and direct protein-protein interaction (PPI) network construction were performed to identify the biological pathways associated with the differentially expressed proteins (DEPs). ELPS treatment induced age-dependent spatial cognitive deficits. In juvenile rats, ELPS caused mild impairments in spatial learning, as reflected by increased escape latency during specific training days, but did not affect spatial memory. In contrast, adult rats exhibited significant and robust impairments in both spatial learning and spatial memory, with longer escape latency across training days, fewer platform crossings, and reduced time and distance in the target quadrant. These findings demonstrate that ELPS-induced cognitive dysfunction is far more pronounced in adult animals, representing persistent and progressive spatial learning and memory deficits. After therapy, 71 proteins were found in the hippocampal region, including 10 DEPs across the juvenile and adult groups post-treatment. Subsequent pathway analysis indicated the involvement of 4 DEPs in various pathways, including Biosynthesis of amino acids, Prion disease, HIF-1 signaling pathway, Distal axon, Alzheimer disease, and Necroptosis pathways. Our study revealed significant proteomic changes in the hippocampus of rats as they transitioned from juveniles to adults, including 10 consistently differentially expressed proteins. These proteomic alterations correspond to the age-dependent spatial cognitive deficits induced by ELPS-mild spatial learning impairment in juveniles and more pronounced deficits in both spatial learning and memory in adults-collectively supporting the lasting effects of ELPS on spatial cognitive function.},
}

@article {pmid42149389,
year = {2026},
author = {Gautam, AS and Singh, RK},
title = {Chrysin Ameliorated Neurochemical and Behavioural Changes Mediated By Combined Exposure of Interleukin-17 A With Amyloid Beta1-42 in Mice.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {21},
number = {1},
pages = {},
pmid = {42149389},
issn = {1557-1904},
mesh = {Animals ; *Amyloid beta-Peptides/toxicity/administration & dosage ; *Flavonoids/pharmacology/therapeutic use ; Mice ; *Interleukin-17/toxicity/administration & dosage ; Male ; *Peptide Fragments/toxicity/administration & dosage ; Mice, Inbred BALB C ; *Alzheimer Disease/metabolism/chemically induced/drug therapy ; Brain/drug effects/metabolism ; },
abstract = {Neuroinflammation is one of the major hallmarks of neurodegenerative diseases, including Alzheimer's disease (AD). Interleukin-17 (IL-17) cytokine and its downstream signaling have been shown to be implicated in preclinical and clinical models of AD. Moreover, the combination of recombinant IL-17 A with amyloid beta (Aβ1-42) has been shown to be involved in promoting neuroinflammation during AD pathology. Hence, it is speculated that IL-17 may exacerbate Aβ1-42-induced neuronal damage and inflammatory events in the brain. Although natural flavonoids have been reported to protect against neuroinflammation in AD, their role in IL-17 exacerbated Aβ1-42-induced responses has not been reported previously. The current research explored the ability of Chrysin in regulating the exacerbation of neuronal damage and inflammation during AD pathology induced due to the combination of recombinant mouse IL-17 A (rmIL-17 A) with Aβ1-42 in animals. Adult male BALB/c mice were exposed to intranasal Aβ1-42 (5 µg/10µL in phosphate-buffered saline (PBS)/animal) and rmIL-17 (4 µg/kg in 10 µL PBS/animal) from day 1 to day 14 on alternate days with therapeutic oral administration of Chrysin suspension (100 mg/kg) during the last 7 days. Oral treatment with Chrysin demonstrated significant protective effects in improving the memory functions of the animals, along with the modulation of neurodegenerative and neuroinflammatory signalling, microglial and astrocytic activation, and redox balance in the hippocampus and cortex areas of the animal brain tissues. These results supported the neuroprotective ability of Chrysin against the exacerbation caused by rmIL-17 A in Aβ1-42-induced AD in a mouse model.},
}

Animals
*Amyloid beta-Peptides/toxicity/administration & dosage
*Flavonoids/pharmacology/therapeutic use
Mice
*Interleukin-17/toxicity/administration & dosage
Male
*Peptide Fragments/toxicity/administration & dosage
Mice, Inbred BALB C
*Alzheimer Disease/metabolism/chemically induced/drug therapy
Brain/drug effects/metabolism

@article {pmid42149841,
year = {2026},
author = {Guu, TW and Li, WJ and Lee, SH and Hsu, CS and Chou, CN and Lack, L and Ma, WF},
title = {Facilitating the measurement and treatment of Behavioral and Psychological Symptoms of Dementia (BPSD) and understanding caregiver burden using wearable devices in Rural Taiwan-Protocol for a dyadic feasibility pilot study.},
journal = {PloS one},
volume = {21},
number = {5},
pages = {e0342136},
pmid = {42149841},
issn = {1932-6203},
mesh = {Humans ; Pilot Projects ; *Caregivers/psychology ; Taiwan ; *Wearable Electronic Devices ; *Dementia/psychology/therapy ; Female ; Male ; Feasibility Studies ; Aged ; Quality of Life ; Surveys and Questionnaires ; Rural Population ; Alzheimer Disease/psychology ; Middle Aged ; Depression ; *Caregiver Burden/psychology ; Actigraphy ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) prevalence rises with societal ageing. In clinical care, behavioral and psychological symptoms of dementia (BPSD)-including depression, agitation/aggression, apathy, and sleep disturbance-worsen patients' quality of life and substantially increase caregiver burden, more significantly than the cognitive symptoms. Standard BPSD assessments rely on caregiver-rated questionnaires that are cross-sectional and may be biased when caregivers are themselves older adults. Device-based measures (e.g., research-grade wrist actigraphy) can provide objective longitudinal data and novel features. In parallel, therapeutic wearables may improve sleep and mood in adults, and might improve BPSD if accepted by people living with dementia.

METHODS: This dyadic pilot study will recruit 20 participants (n = 10 AD patients; n = 10 caregivers) from outpatient services and affiliated day-care/dementia hubs in rural Taiwan. Participants will wear Geneactiv continuously for 8 weeks and Re-Timer ≥30 min/day for 4 weeks. Device-based data will be processed with GGIR, a well validated R-package designed for processing accelerometer data. Questionnaire assessments include Pittsburgh Sleep Quality Index (PSQI), Neuropsychiatry Inventory Questionnaire (NPI-Q), Caregiver Burden Inventory (CBI), and a semi-structured interview based on the Taiwanese version of Quebec User Evaluation of Satisfaction with Assistive Technology (T-QUEST) at prespecified timepoints.

DISCUSSION: Wearable devices may facilitate the measurement and treatment of specific BPSD, as well as reduce caregiver burden. If proven feasible even in rural Taiwan where both digital and health literacy and resources are limited, this model will inform how device-based dementia care model can be considered and applied in the context of global ageing.},
}

Humans
Pilot Projects
*Caregivers/psychology
Taiwan
*Wearable Electronic Devices
*Dementia/psychology/therapy
Female
Male
Feasibility Studies
Aged
Quality of Life
Surveys and Questionnaires
Rural Population
Alzheimer Disease/psychology
Middle Aged
Depression
*Caregiver Burden/psychology
Actigraphy

@article {pmid42151713,
year = {2026},
author = {Stijven, F and Mallinckrodt, C and Molenberghs, G and Alonso, A and Dickson, SP and Hendrix, SB},
title = {Time-Scale Target Parameters and Two-Step Estimation in Longitudinal Trials for Progressive Diseases.},
journal = {Statistics in medicine},
volume = {45},
number = {10-12},
pages = {e70591},
doi = {10.1002/sim.70591},
pmid = {42151713},
issn = {1097-0258},
support = {//Agentschap Innoveren en Ondernemen/ ; HBC.2022.0145//Johnson & Johnson Innovative Medicine/ ; },
mesh = {Humans ; *Disease Progression ; Longitudinal Studies ; Alzheimer Disease/drug therapy/therapy ; *Randomized Controlled Trials as Topic/statistics & numerical data/methods ; Computer Simulation ; Models, Statistical ; Time Factors ; Treatment Outcome ; Data Interpretation, Statistical ; },
abstract = {In progressive diseases such as Alzheimer's, treatments that slow progression should start early to preserve higher levels of functioning for a longer period. In corresponding clinical trials, treatment effects are usually expressed as mean differences on a clinical scale at fixed time points. Early in the disease course, however, these mean differences may appear small but may nonetheless correspond to an important slowing of disease progression. This complicates the appreciation of the relevance of observed treatment effects. We introduce a class of target parameters that quantify treatment effects on the time scale in longitudinal studies; for instance, in terms of time saved or percentage slowing of progression. We focus on data from randomized trials where the target parameters are identified under regularity assumptions. These target parameters remain well defined if treatment was not randomized, but additional untestable assumptions are required for identification. We propose general two-step estimators. In the first step, the data can be analyzed with standard methods for longitudinal data and standard software can thus be used. In the second step, summary statistics from the first step are used for inferences about the target parameters. The second step has been implemented in the TCT R package. We study the asymptotic properties and efficiency of these two-step estimators, and evaluate them in an extensive simulation study. These estimators are used in a phase 2/3 clinical trial for Alzheimer's disease, leading to important additional insights into the treatment effect.},
}

Humans
*Disease Progression
Longitudinal Studies
Alzheimer Disease/drug therapy/therapy
*Randomized Controlled Trials as Topic/statistics & numerical data/methods
Computer Simulation
Models, Statistical
Time Factors
Treatment Outcome
Data Interpretation, Statistical

@article {pmid42151732,
year = {2026},
author = {Hammers, DB and Foster, E and Eloyan, A and Thangarajah, M and Taurone, A and Touroutoglou, A and La Joie, R and Beckett, L and Gao, S and Vemuri, P and Nudelman, KN and Kirby, K and Dage, JL and Aisen, P and Atri, A and Clark, D and Day, GS and Duara, R and Graff-Radford, NR and Grant, I and Honig, LS and Johnson, ECB and Jones, DT and Masdeu, JC and Mendez, MF and Parand, L and Womack, K and Musiek, E and Onyike, CU and Riddle, M and Rogalski, E and Salloway, S and Sha, SJ and Turner, RS and Wingo, TS and Wolk, DA and Dickerson, BC and Rabinovici, GD and Carrillo, MC and Apostolova, LG and , },
title = {Cognitive dispersion profiles and prediction of cognitive change in early-onset dementias: Results from LEADS.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71492},
doi = {10.1002/alz.71492},
pmid = {42151732},
issn = {1552-5279},
support = {AARG-22-926940/ALZ/Alzheimer's Association/United States ; LDRFP-21-818464/ALZ/Alzheimer's Association/United States ; K23 AG080071/ALZ/Alzheimer's Association/United States ; R56 AG057195/ALZ/Alzheimer's Association/United States ; U01AG6057195/ALZ/Alzheimer's Association/United States ; U24AG021886/ALZ/Alzheimer's Association/United States ; U01 AG016976/ALZ/Alzheimer's Association/United States ; P30 AG010133/ALZ/Alzheimer's Association/United States ; P50 AG008702/ALZ/Alzheimer's Association/United States ; P50 AG025688/ALZ/Alzheimer's Association/United States ; P50 AG005146/ALZ/Alzheimer's Association/United States ; P30 AG062421/ALZ/Alzheimer's Association/United States ; P30 AG062422/ALZ/Alzheimer's Association/United States ; P50 AG023501/ALZ/Alzheimer's Association/United States ; P30 AG010124/ALZ/Alzheimer's Association/United States ; P30AG066506/ALZ/Alzheimer's Association/United States ; P30 AG013854/ALZ/Alzheimer's Association/United States ; P50 AG005681/ALZ/Alzheimer's Association/United States ; P50AG047366/ALZ/Alzheimer's Association/United States ; U24AG021886/ALZ/Alzheimer's Association/United States ; R56AG057195/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Female ; Male ; Neuropsychological Tests/statistics & numerical data ; *Dementia/psychology ; *Cognition/physiology ; Biomarkers ; Middle Aged ; *Alzheimer Disease/psychology ; Age of Onset ; },
abstract = {INTRODUCTION: Research into cognitive dispersion - a cognitive process score measuring the intra-individual variability (IIV) across a single testing session - suggests utility in neurodegenerative populations. Given widespread deficits observed in sporadic early-onset Alzheimer's disease (EOAD), however, it is unclear if examining cognitive dispersion shows benefit in this condition.

METHODS: A total of 309 participants (188 amyloid-positive EOAD, 43 amyloid-negative early-onset dementia [EOnonAD], 78 cognitively normal [CN]) completed neuropsychological testing twice over 12 months. Dispersion-related differences among groups were assessed, as was cognitive dispersion's capacity to predict domain-specific cognitive trajectories, and its convergence with imaging biomarkers.

RESULTS: EOAD participants displayed higher cognitive dispersion than EOnonAD participants, and associations with EOAD-specific biomarkers. Additionally, cognitive dispersion was associated with 12-month reliable change across several cognitive domains.

DISCUSSION: These preliminary results examine cognitive dispersion in sporadic EOAD. When used with baseline cognitive performance, cognitive dispersion measures may enrich future clinical trials in EOAD by enhancing treatment monitoring over time.},
}

Humans
Female
Male
Neuropsychological Tests/statistics & numerical data
*Dementia/psychology
*Cognition/physiology
Biomarkers
Middle Aged
*Alzheimer Disease/psychology
Age of Onset

@article {pmid42151912,
year = {2026},
author = {Stuardo, N and Cáceres-Quezada, Á and Guzmán, D and Lamaizon, CM and Leal R, N and Koleske, AJ and Álvarez R, A},
title = {Abl kinase activation promotes axon initial segment disassembly and protein sorting defects in Alzheimer's disease.},
journal = {BMC biology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12915-026-02624-5},
pmid = {42151912},
issn = {1741-7007},
abstract = {BACKGROUND: Axon initial segment (AIS) dysfunction disrupts neuronal compartmentalization, which leads to pathological processes like Tau missorting in Alzheimer's disease (AD). However, the molecular mechanisms that destabilize the AIS scaffold are incompletely understood. Our group has previously shown that the Abl1 non-receptor tyrosine kinase is aberrantly activated in AD mouse models and promotes dendritic spine collapse, Tau hyperphosphorylation, and neuronal apoptosis. Given the important role of Abl1 in AD and its emerging significance in Tau pathology, we examined how it contributes to AIS collapse.

RESULTS: We find that activation of Abl1 by amyloid-β fibrils promotes AIS disruption, as determined by the loss of clustered AnkG in the proximal axon, and that this can be prevented by pharmacological inhibition of Abl kinases. Cytosolic extraction experiments show that active Abl1 associates to the AIS scaffold, and this association increases in response to amyloid-β fibril treatment. Furthermore, using expansion microscopy, we show that Abl1 localizes to the AIS in dissociated hippocampal cultures and in mouse brain slices. We find a decrease in AIS actin patches, key for maintenance of neuronal compartmentalization, following Abl kinase activation. Finally, we show that Abl1 activation promotes missorting of somatodendritic Rab11 into the axon and the axonal protein Tau into the somatodendritic compartment, indicating a bidirectional failure in AIS barrier function.

CONCLUSIONS: Taken together, our results show that Abl1 plays an important role in AIS destabilization and that its activation compromises protein compartmentalization in a primary neuron culture model of AD.},
}

@article {pmid42151941,
year = {2026},
author = {Luo, M and Zhao, FK and Wang, YM and Bian, J and Luo, Y},
title = {Bibliometric analysis of nanomaterials in the diagnosis and treatment of neurological and psychiatric disorders (1997-2025): trends and future directions.},
journal = {Journal of nanobiotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12951-026-04529-5},
pmid = {42151941},
issn = {1477-3155},
support = {Zunyi Science and Technology Talent Team Project [2024] No. 6//Zunyi Science and Technology Bureau/ ; No. 39 (2023)//Zunshi Science and Technology Cooperation Letter/ ; (QZYY-2024-094)//Science and technology research topic of traditional Chinese medicine and ethnic medicine of Guizhou Provincial Administration of Traditional Chinese Medicine/ ; No: 24QNMP019//Health Commission of Sichuan Province Medical Science and Technology Program/ ; 25MSZX259//Scientific Research Projects of the Sichuan Provincial Administration of Traditional Chinese Medicine/ ; 2026NSFSC1634//Sichuan Province Natural Science Foundation/ ; },
abstract = {Nanomaterials have demonstrated substantial promise in the diagnosis and treatment of neurological and psychiatric disorders, offering novel strategies to overcome the limitations of traditional therapies. This review utilizes bibliometric analysis to evaluate global trends in nanomaterial research for neurological and psychiatric diseases, based on a corpus of 3,987 publications retrieved from the Web of Science Core Collection spanning from 1997 to August 2025. The analysis reveals a consistent upward trajectory in annual publications, reflecting substantial and growing international interest across diverse regions. Following an overview of global research dynamics, this review explores the pathogenesis of neurological and psychiatric disorders, such as Alzheimer's disease, Parkinson's disease, depression, and schizophrenia. The mechanisms underlying these conditions, including neuroinflammation, oxidative stress, protein aggregation, and neurotransmitter imbalances, are systematically discussed. Subsequently, the review focuses on how nanomaterials, including nanoparticles, nanocomposites, and nanocarriers, target these pathogenic mechanisms. The therapeutic applications of nanomaterials are evaluated with respect to their ability to modulate neuroinflammation, reduce oxidative stress, improve drug delivery to the brain, and facilitate the repair of neuronal damage. Despite the promising potential of nanomaterials, several challenges remain, including biocompatibility, targeted delivery, and scalability of treatment options. The review concludes by highlighting future directions for research, emphasizing the need for continued innovation in nanomaterial design and application to address these challenges and advance clinical treatments for neurological and psychiatric disorders.},
}

@article {pmid42152119,
year = {2026},
author = {Skácelíková, E and Vyhnálek, M and Děchtěrenko, F and Nikolai, T and Veverová, K},
title = {Willingness and barriers to blood-based biomarker testing of Alzheimer's disease in the general population in the Czech Republic.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02070-z},
pmid = {42152119},
issn = {1758-9193},
support = {PTC-Gene-25-1439553//Alzheimer's Association - Part the Cloud Translational Research Program/ ; PTC-Gene-25-1439553//Alzheimer's Association - Part the Cloud Translational Research Program/ ; CZ.02.01.01/00/22_008/0004595//European Regional Development Fund, under the project "Beyond Security: Role of Conflict in Resilience-Building"/ ; },
abstract = {BACKGROUND: Blood-based biomarkers (BBBM) for Alzheimer's disease (AD) are entering clinical practice with new clinical practice guidelines and the first FDA-approved blood test. Their implementation will depend not only on assay performance but also on public willingness, trust, and understanding of probabilistic results. We examined attitudes towards BBBM in the general population and psychosocial factors that may facilitate or hinder uptake.

METHODS: We conducted an online cross-sectional survey among adults aged ≥ 35 years (M = 51.08, SD = 9.79) in the Czech Republic (N = 666). The survey assessed willingness to undergo BBBM testing, sociodemographic characteristics, experience with AD, depressive symptoms (Patient Health Questionnaire, PHQ-9), concerns about developing AD, and medical distrust (Medical Distrust Index, MDI). Logistic regression models (unweighted and weighted for gender and region) were estimated to examine the association with willingness. Open-ended responses were analyzed thematically to identify motivators and barriers.

RESULTS: Overall, 92.8% of participants reported that they would undergo BBBM testing. Greater concern about developing AD was the strongest facilitator (OR = 1.59-2.34). Having AD in a close family member was associated with lower willingness (OR = 0.31-0.43), as was higher medical distrust (MDI OR = 0.79 in the fully weighted model). Education, age, gender, depressive symptoms, and AD knowledge were not significantly associated with willingness. Qualitative analyses showed that participants viewed BBBM as a way to "take action in time", "know one's health status" and "prepare for the future", whereas fear of AD, preference "not to know", perceived lack of treatment, test uncertainty/"only probability", and privacy concerns were common barriers.

CONCLUSIONS: Public willingness to undergo BBBM testing is high, but psychosocial barriers, particularly familial experience of AD and medical distrust, may limit real-world uptake. Addressing these barriers through targeted education, probabilistic risk communication, and trusted primary-care pathways will be essential for the responsible implementation of BBBM in clinical practice.},
}

@article {pmid42142451,
year = {2026},
author = {Razavi, A and Hou, J and Lin, SJ and Zhang, C and Kremen, WS and Fennema-Notestine, C and Elman, J and Holmans, P and Faraone, SV and Gaiteri, C and Hess, JL and Glatt, SJ},
title = {Predicted brain-regional gene expression patterns in individuals living with Alzheimer's disease.},
journal = {Neurobiology of aging},
volume = {166},
number = {},
pages = {29-40},
doi = {10.1016/j.neurobiolaging.2026.04.006},
pmid = {42142451},
issn = {1558-1497},
abstract = {Studying brain gene expression in Alzheimer's Disease (AD) remains difficult as postmortem brain is difficult to access, cannot be used to guide donor treatment, may be confounded by environmental factors before and after death, and is difficult to link to early AD states or disease progression. To circumvent these limitations, several studies have tested blood transcriptome biomarkers for AD. However, gene-expression levels in the blood have limited correlation with those in the brain. To evaluate the potential of monitoring Alzheimer's progression with peripheral data, we used transcriptome-imputation to identify brain-region-specific AD-associated gene-expression differences in cohorts with blood-based transcriptome data. This approach provides a high-resolution image of AD-associated molecular differences in the brains of individuals actively living with disease. We analyzed eight AD studies (777 AD cases, 779 cognitively unimpaired controls), imputing transcriptomes in 10 brain regions via the Brain Gene Expression and Network Imputation Engine (BrainGENIE). Hundreds of differentially expressed genes (DEGs) associated with AD were identified in nine brain regions, with anterior cingulate cortex and amygdala showing the most differential expression. AD-associated genes were enriched in pathways such as proteostasis, mitochondrial dysfunction, and immune activation. We observed significant yet moderate concordance between imputed AD-associated changes and those directly measured in the dorsolateral prefrontal cortex and cerebellum. These transcriptomic changes can guide future in vitro studies focused on pathogenesis or be targets of novel therapeutic development. In conclusion, we demonstrated the scope and utility of brain expression imputation from the peripheral transcriptome, laying the groundwork for biomarker discovery and prospective AD studies.},
}

@article {pmid42142620,
year = {2026},
author = {Shang, X and Chen, SY and Zhang, XY and Regina, I and Zhang, T and Luo, J and Yan, YZ and Qiao-yuanYao, and Tong, F and Pan, LH},
title = {Insulin in brain: The physiological functions and therapeutic insights for neurodegenerative diseases.},
journal = {Life sciences},
volume = {398},
number = {},
pages = {124468},
doi = {10.1016/j.lfs.2026.124468},
pmid = {42142620},
issn = {1879-0631},
abstract = {This review highlight the function of insulin in the central nervous system in addition to its role in the periphery. The cerebral distribution and mechanisms of insulin and its receptor isoforms are reviewed in detail. We emphasize the essential roles of insulin in the maintenance of cerebral glucose homeostasis, modulation of cognitive performance, regulation of appetite, promotion of cerebrovascular angiogenesis, and exertion of neuroprotective effects. We demonstrate how insulin resistance exacerbates characteristic neuropathological features in Alzheimer's disease (AD) and Parkinson's disease (PD), while insulin-based interventions ameliorate these pathologies through multiple mechanisms including increasing the activity of insulin-degrading enzyme, suppressing Aβ neurotoxicity, and reducing α-synuclein deposition. The review also systematically examines the neuroprotective effects of insulin sensitizers and their potential to reduce the risk of AD, while noting the complexity of their bidirectional regulatory role in PD, which warrants further investigation. Notably, intranasal insulin administration emerges as a promising non-invasive therapeutic approach that bypasses the blood-brain barrier via olfactory and trigeminal pathways, suggesting significant potential for cognitive enhancement and neuropathological mitigation. Nonetheless, it must be noted that the optimal dosage, long-term safety, and sustained efficacy of insulin therapy remain unclear, and the current evidence is derived primarily from preclinical studies or small-scale clinical trials. In summary, this review paper underscores the critical physiological roles of insulin in the brain and outlines novel therapeutic strategies for using insulin in the treatment of AD and PD.},
}

@article {pmid42142765,
year = {2026},
author = {Feng, Y and Zhang, C and Wei, Y and Liu, E and Sun, H and Flatt, P and Gault, V and Irwin, N and Hölscher, C and Hao, L and Zhang, Z},
title = {A novel bifunctional peptide predicted to target neuropeptide Y4 and GLP-1 receptors alleviates cognitive deficits in 5 × FAD mice by modulating cGAS-STING-mediated neuroinflammation.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118074},
doi = {10.1016/j.bcp.2026.118074},
pmid = {42142765},
issn = {1873-2968},
abstract = {Effective disease-modifying therapies for Alzheimer's disease (AD) remain limited. Glucagon-like peptide-1 receptor (GLP-1R) activation has shown neuroprotective potential in AD, whereas the neuropeptide Y/pancreatic polypeptide-Y4 receptor (NPY/PP-Y4R) axis has been implicated in central homeostasis and inflammatory regulation, although its role in AD remains insufficiently defined. Here, we evaluated a rationally designed bifunctional peptide predicted to target both NPY4R and GLP-1R in 5 × FAD mice and LPS-stimulated BV2 cells. In vivo, NPY4/GLP-1 improved spatial learning and memory, working memory, and exploratory behavior, and was accompanied by reduced hippocampal Aβ burden (P < 0.05), alleviated neuronal injury (P < 0.01), improved synaptic integrity (P < 0.01), and attenuated mitochondrial abnormalities (P < 0.01). These changes were associated with lower hippocampal levels of cytosolic mitochondrial DNA (mtDNA) (P < 0.05), cGAS (P < 0.05), STING (P < 0.05), and phosphorylated IRF3 (P < 0.01), together with decreased IL-1β (P < 0.05) and increased IL-10 (P < 0.05) expression. In LPS-stimulated BV2 cells, NPY4/GLP-1 similarly reduced STING-related signaling (P < 0.05) and inflammatory responses (P < 0.05). Co-treatment with the STING inhibitor C-176 provided additional support for the involvement of STING-associated inflammatory signaling under in vitro inflammatory conditions. Molecular docking suggested that NPY4/GLP-1 may interact with both NPY4R and GLP-1R, providing a structural rationale for its bifunctional design. Collectively, these findings indicate that NPY4/GLP-1 exerts beneficial effects in AD-related models and that these effects are associated with attenuation of mtDNA-cGAS-STING-related neuroinflammatory signaling. This study provides initial evidence supporting further evaluation of this novel bifunctional peptide as a candidate therapeutic strategy for AD.},
}

@article {pmid42143322,
year = {2026},
author = {Gröbner, LS and Pietrzik, CU},
title = {Transport pathways across the blood-brain barrier for waste clearance and drug delivery.},
journal = {Fluids and barriers of the CNS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12987-026-00812-7},
pmid = {42143322},
issn = {2045-8118},
abstract = {The blood-brain barrier (BBB) displays a highly organized and complex structure, which is important for maintaining brain homeostasis and protecting the brain from foreign molecules or pathogens. Receptor-mediated transcytosis (RMT) is one of the main delivery pathways across the BBB for molecules that cannot pass the barrier via, e.g. paracellular diffusion. For understanding the treatment options in neurodegenerative diseases such as Alzheimer´s disease (AD), it is important to investigate transport pathways and mechanisms at the BBB for a potential delivery of drugs, antibodies or other compounds across the BBB. This review provides an overview of the different transport variants across the BBB and how they can be targeted in order to promote internalization or secretion into or out of the brain. Therefore, we want to focus on two characterized proteins: the low-density lipoprotein receptor-related protein 1 (LRP1), which is a key mediator of amyloid β (Aβ) clearance from the brain during AD, and transferrin receptor 1 (TfR1), which is already used as a target for antibody-delivery into the brain. Additionally, this review discusses two other important proteins, which have been less frequently addressed in research regarding transport mechanisms: P-glycoprotein (P-gp) as another transporter at the BBB and proprotein convertase subtilisin/kexin type 9 (PCSK9), a well-known regulator of cholesterol homeostasis which promotes the degradation of the low-density lipoprotein receptor (LDLR) and LRP1. For these four main proteins, we aim to highlight existing approaches for targeting or inhibiting the aforementioned receptors or proteins. The approaches enable a higher penetration of the BBB, a better distribution in the brain, and ultimately fewer side effects of antibodies or nanoparticles. Here, we include lecanemab, trontinemab, dual TfR/CD98hc shuttles, evolocumab and alirocumab, immunoliposomes and other nanoparticles targeting TfR1 or LRP1. We will further highlight approaches which differ from these common ideas and demonstrate the current state of the art regarding drug delivery and waste clearance across the BBB.},
}

@article {pmid42144109,
year = {2026},
author = {Loukil, I and Vachon, A and Çaku, A and Plourde, M},
title = {Krill oil increase plasma omega-3 fatty acids more than fish oil in healthy adults: a double blind randomized controlled trial.},
journal = {The American journal of clinical nutrition},
volume = {},
number = {},
pages = {101346},
doi = {10.1016/j.ajcnut.2026.101346},
pmid = {42144109},
issn = {1938-3207},
abstract = {BACKGROUND: Omega-3 fatty acids (ω-3 FAs), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are recognized for their health benefits. However, their circulating levels after supplementation may be modulated by several factors, including sex, carriage of the apolipoprotein E4 allele (APOE4), and the chemical form of the supplement. Krill-oil delivers ω-3 FAs primarily as phospholipids (PL), whereas fish oil provides them as triglycerides (TG).

OBJECTIVE: To compare EPA and DHA concentrations after a supplementation with krill oil and fish oil and assess whether sex and APOE4 genotype modifies responses to supplementation.

METHODS: This double-blind, randomized clinical trial included 72 healthy adults (53 females, 19 males) matched for age and body mass index (BMI). Participants received 1.1 g/day ω-3 FAs through either krill oil (n=36) or fish oil (n=36) for 12 weeks. Plasma fatty acids were measured at baseline and at weeks 1, 2, 4, and 12 by gas chromatography-flame ionization detection. Differences in plasma ω-3 FAs concentrations by treatment, sex and APOE4 status, were analyzed.

RESULTS: Time-by-treatment interactions were significant for plasma delta over baseline concentrations of EPA (p = 0.0001) and DHA (p = 0.005), with krill oil resulting in ∼ 1.5-fold higher ΔEPA and ΔDHA compared to fish oil. The time-by-sex interaction was significant only for EPA (p = 0.026), with females having 1.5-fold greater increase than males at 12 weeks. Following supplementation with either krill oil or fish oil, APOE4 carriers had 3-fold and 1.6-fold higher EPA and DHA respectively, compared to baseline; however, these increases were not significantly different from those found in non-carriers.

CONCLUSIONS: Krill oil increased plasma ω-3 FAs more than fish oil, regardless of APOE4 genotype. Individuals with higher ω-3 FA requirements may achieve adequate enrichment with lower doses of krill oil compared to fish oil supplementation.

REGISTRATION NUMBER: NCT04279743. In https://clinicaltrials.gov.},
}

@article {pmid42144687,
year = {2026},
author = {Zhao, Q and Yu, Y and Wang, F and Wang, Y and Shao, P and Zhao, L},
title = {TARDBP Mediates the MAP3K11/SLC3A2/GPX4 Axis in Alzheimer's Disease Rats by Enhancing KRAS mRNA Stability.},
journal = {Journal of cellular and molecular medicine},
volume = {30},
number = {10},
pages = {e71181},
doi = {10.1111/jcmm.71181},
pmid = {42144687},
issn = {1582-4934},
support = {HAB202113//Huai'an Natural Science Research Program/ ; },
mesh = {Animals ; Rats ; *Alzheimer Disease/metabolism/genetics/pathology ; PC12 Cells ; *RNA Stability/genetics ; *Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism/genetics ; *Proto-Oncogene Proteins p21(ras)/genetics/metabolism ; Male ; Hippocampus/metabolism/pathology ; Disease Models, Animal ; Ferroptosis/genetics ; Amyloid beta-Peptides ; Reactive Oxygen Species/metabolism ; Iron/metabolism ; RNA, Messenger/genetics/metabolism ; Rats, Sprague-Dawley ; Signal Transduction ; },
abstract = {Ferroptosis is an emerging pathological mechanism in Alzheimer's disease (AD). The aim of the present study was to investigate the potential mechanisms by which TARDBP is involved in AD by promoting ferroptosis. An AD rat model was established by injecting homocysteine (Hcy). Memory function was assessed using the Morris water maze test and contextual fear conditioning test. Hippocampal neurons' morphology was observed by HE staining, and intracellular iron deposition in the hippocampus was evaluated by Perls' blue staining. PC12 cells were treated with 20 μM Aβ1-42 to establish an AD cell model in vitro. Cell viability was measured by MTT assay; LDH release, intracellular ROS levels and Fe[2+] concentrations were determined. The mRNA stability of KRAS was assessed by actinomycin D assay. Activation of the MAP3K11/SLC3A2/GPX4 pathway was assessed by Western blot. Treatment with Fer-1 or down-regulation of TARDBP improved memory function and reduced intracellular iron deposition in the hippocampus of AD rats. Furthermore, these interventions inhibited Aβ1-42-induced PC12 cell damage, ROS production and iron accumulation. Mechanistically, down-regulating TARDBP reduced the mRNA stability of KRAS, inhibited MAP3K11 expression and subsequently promoted the expression of SLC3A2 and GPX4. Conversely, up-regulation of KRAS reversed the protective effects induced by TARDBP knockdown in both AD rats and Aβ1-42-induced PC12 cells. TARDBP promotes the development of AD by enhancing the mRNA stability of KRAS, thereby mediating the MAP3K11/SLC3A2/GPX4 axis to induce ferroptosis.},
}

Animals
Rats
*Alzheimer Disease/metabolism/genetics/pathology
PC12 Cells
*RNA Stability/genetics
*Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism/genetics
*Proto-Oncogene Proteins p21(ras)/genetics/metabolism
Male
Hippocampus/metabolism/pathology
Disease Models, Animal
Ferroptosis/genetics
Amyloid beta-Peptides
Reactive Oxygen Species/metabolism
Iron/metabolism
RNA, Messenger/genetics/metabolism
Rats, Sprague-Dawley
Signal Transduction

@article {pmid42145109,
year = {2026},
author = {Saxena, P and Kothiyal, P and Ratan, P},
title = {Evaluation of neuroprotective effects of Pyracantha crenulata (D. Don) M. Roem against aluminium chloride induced memory impairment of rats.},
journal = {Neurological research},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/01616412.2026.2673060},
pmid = {42145109},
issn = {1743-1328},
abstract = {Pyracantha crenulata, traditionally used in Himalayan folk medicine, valued for enhancing vitality, mental clarity, and combating age-related cognitive decline due to its antioxidant constituents.

AIM: This study evaluated the neuroprotective effect of hydroalcoholic extract of P. crenulata against aluminium chloride (AlCl3)-induced Alzheimer's disease in rats.

MATERIALS AND METHODS: Alzheimer's pathology was induced using AlCl3, and rats were treated with P. crenulata extract (250 and 500 mg/kg) for 21 days. Cognitive and behavioural performance were assessed using the Morris Water Maze (MWM) and Elevated Plus Maze (EPM). Biochemical parameters, including oxidative stress markers (SOD), cholinesterase activity (AChE), and myeloperoxidase levels (MPO), were measured. Histopathological examination of the hippocampus and cerebral cortex was conducted.

RESULTS: Aluminium intoxication led to marked deficits in learning and memory, as evidenced by performance in the Morris Water Maze and Elevated Plus Maze tests. Treatment with P. crenulata extract significantly enhanced spatial and long-term memory in a dose-dependent manner, with the higher dose producing the most pronounced improvement.

CONCLUSION: The findings of this study highlight the notable neuroprotective effects of P. crenulata, demonstrated through modulation of biochemical parameters and suppression of amyloid precursor protein and Tau, key pathological hallmarks of Alzheimer's disease, further validated by histopathological evidence.},
}

@article {pmid42145110,
year = {2026},
author = {Wimo, A and Jönsson, L},
title = {[Health economic aspects of dementia].},
journal = {Lakartidningen},
volume = {123},
number = {},
pages = {},
pmid = {42145110},
issn = {1652-7518},
mesh = {Humans ; *Dementia/economics/diagnosis/epidemiology ; Sweden/epidemiology ; Cost-Benefit Analysis ; Health Care Costs ; Cost of Illness ; Quality of Life ; Alzheimer Disease/economics ; Life Expectancy ; },
abstract = {The societal costs of dementia in Sweden are very high: about SEK 90-100 billion per year. A purely demographic projection to 2050 gives a cost increase of about 80%. In addition to the costs, dementia also entails a loss of life expectancy for those with dementia and of quality of life for those affected and their relatives. At present, it is not possible to assess whether the antibody treatment against Alzheimer's disease is cost-effective in Sweden because no price is yet available. Blood-based biomarkers for Alzheimer's disease and other diagnostic methods, if included in the pricing basis for new drugs, can be a valuable addition to cost-effectiveness analyses.},
}

Humans
*Dementia/economics/diagnosis/epidemiology
Sweden/epidemiology
Cost-Benefit Analysis
Health Care Costs
Cost of Illness
Quality of Life
Alzheimer Disease/economics
Life Expectancy

@article {pmid42145619,
year = {2026},
author = {Sherva, R and Bayly, H and Zhang, R and Harrington, K and Mez, J and Miller, MW and Tsuang, D and Wolf, E and Zeng, Q and Le Guen, Y and Tejeda, M and , and , and , and Gaziano, JM and Panizzon, MS and Hauger, RL and Merritt, VC and Farrer, LA and Logue, MW},
title = {A Genome-wide Association Study of Alzheimer's Disease and Dementia in a Large Multi-ancestry Military Cohort Identifies Many New Dementia-Associated Loci.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.01.26352216},
pmid = {42145619},
abstract = {INTRODUCTION: Biobank-scale cohorts of individuals with genetic data and diagnoses of Alzheimer's disease and related dementias (ADRD) have facilitated the discovery of additional risk loci via meta-analysis, with existing cohorts assembled specifically for ADRD genetic discovery. Cross-ancestry meta-analyses have further elucidated the overall genetic architecture of these dementias. Here, we include for the first time the European ancestry (EA) and Hispanic ancestry (HA) subset of the VA Million Veterans Program (MVP) along with the African ancestry (AA) MVP participants in a meta-analysis with a large-scale EA and AA meta-analysis.

METHODS: Independent genome-wide association studies (GWASs) were conducted in MVP participants using four phenotypes derived from electronic medical records and surveys: ADRD, prescriptions for common dementia medications, and self-reported maternal and paternal history of dementia (dementia by proxy). These GWASs were repeated in the EA, AA, and HA cohorts. MVP ancestry-specific and cross-ancestry meta-analyses were conducted. These were then meta-analyzed with existing GWAS results. Functionality of the peak variants was explored using brain-derived gene expression data and co-localization analysis.

RESULTS: Apart from the APOE region, 17, 4, and 3 genome-wide significant (GWS) loci were observed in the MVP EA, AA, and HA meta-analyses, respectively. When we meta-analyzed these with consortium results, we observed 72 loci in the EA GWAS, and 62 lead loci in the cross-ancestry meta-analysis. While most of these loci were known, 27 genes/regions were identified containing variants surpassing genome-wide significance for the first time: 7 EA specific, 12 in the cross-ancestry meta-analysis, and 8 driven by AA and HA cohorts. Several of these are members of pathways containing established ADRD risk genes, and several of the peak SNPs showed evidence for eQTL effects on their respective genes. Several of the novel SNPs showed significant eQTL effects in brain-derived mRNA-seq experiments. Additionally, there was a significant differential expression of the novel gene PAX7 in ADRD cases and controls.

DISCUSSION: MVP represents a large and unique primarily male cohort comprised of US Veterans from a range of backgrounds with a unique set of environmental exposures. The results generated here demonstrate the utility of biobank level cohorts for AD genetic discovery. Furthermore, our discovery of ADRD genes was enhanced by the inclusion of MVP data that provided an increase of underrepresented ancestry groups in contrast to prior cross ancestry GWASs. The new AD risk loci identified present potential new targets for dementia treatment confirmed that future large-scale analyses of AD genetic risk and prediction will be enhanced by the inclusion of MVP data.},
}

@article {pmid42145636,
year = {2026},
author = {Lorenzi, M and Custo, A and Frisoni, GB and Garibotto, V},
title = {A data-driven Alzheimer's disease progression simulator for retrospective validation and prospective Phase III power design.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.03.26352317},
pmid = {42145636},
abstract = {Anti-amyloid immunotherapies have recently demonstrated the first significant slowing of cognitive decline in Alzheimer's disease (AD), yet clinical benefit varies markedly across drugs and scales with the completeness of amyloid clearance. Pharmacokinetic/pharmacodynamic (PK/PD) models are currently the standard tool for trial simulation, but they typically operate on single biomarkers and rely on drug-concentration assumptions, leaving the multi-scale cascade from amyloid clearance through tau, neurodegeneration, and cognition largely unmodelled. No existing framework has been jointly validated against the quantitative outcomes of multiple real-world phase III trials, spanning clearance kinetics, multi-modal biomarker trajectories, and statistical power. We present a trial simulation platform based on SimulAD, a disease progression model trained exclusively on longitudinal observational data from ADNI, with no access to trial-arm labels or drug-specific outcomes. SimulAD encodes intervention as piecewise amyloid clearance terms within a latent ordinary differential equation system that jointly governs amyloid, tau, structural MRI, and cognitive trajectories under the amyloid cascade hypothesis. We retrospectively simulated six landmark phase III anti-amyloid trials (TRAILBLAZER-ALZ2, CLARITY AD, EMERGE and ENGAGE, GRADUATE I and GRADUATE II) using a single trained model with trial-specific calibration limited to amyloid clearance kinetics. SimulAD reproduced published mean centiloid reductions within 5% error across all six trials and generated CDR-SB distributions broadly consistent with reported placebo and treated-arm outcomes. In a retrospective power analysis, calibrated simulations separated the three positive from the three null trials, with EMERGE near the decision boundary and ENGAGE and both GRADUATE trials below it. Across trials, higher amyloid-clearance rates were associated with larger calibrated clinical effects and lower estimated sample sizes. These results establish SimulAD as a valid disease-progression-centric trial simulator providing quantitative guidance on sample size planning and treatment kinetics optimisation that is grounded in the full multi-modal biomarker cascade of AD.},
}

@article {pmid42146610,
year = {2026},
author = {Shiferaw, TG and Sarkar, S and Baker, KM and Wooldridge, RS and Binfet, HM and Prozapas, VN and Ogbu, CP and Schepmoes, AA and Attah, IK and Niemeyer, CS and Sprenger, KG and Hassell, JE and Eckel, RH and Melchior, JT and Bruce, KD},
title = {ApoE Lipidation State Directs Immunometabolic Reprogramming of Human Microglia.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.04.722733},
pmid = {42146610},
issn = {2692-8205},
abstract = {INTRODUCTION: ApoE4 is the strongest genetic risk factor for Alzheimer's disease (AD). Emerging evidence suggests that ApoE4 increases AD risk by disrupting microglial metabolism and function. However, whether ApoE lipidation state contributes to microglial dysfunction remains poorly understood.

METHODS: Human microglia were treated with lipid-free or lipid-bound ApoE3 or ApoE4. Label-free live-cell holotomography and global proteomics were used to assess isoform- and lipidation-specific effects on lipid droplet dynamics, mitochondrial morphology, and microglial phenotype.

RESULTS: ApoE4 treatment resulted in fewer but enlarged lipid droplets and increased mitochondrial fragmentation compared to ApoE3, effects that were enhanced by lipid-bound ApoE4. Proteomic analyses revealed a strong type I interferon response in cells exposed to lipid-free ApoE, which was exacerbated by lipid-free ApoE4.

DISCUSSION: These findings indicate that lipid-bound ApoE4 drives metabolic reprogramming, whereas lipid-free ApoE4 promotes inflammatory signaling, identifying ApoE lipidation as a critical modifier of ApoE4-associated AD risk.},
}

@article {pmid42146614,
year = {2026},
author = {Lu, W and Caulfield, TR and Lee, E and Jeevaratnam, S and Wang, N and Bu, G and Kanekiyo, T and Li, Y},
title = {Discovery of a CI-994 derivative as a dual modulator of class I HDACs and Wnt/β-catenin signaling for Alzheimer's disease therapy.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.30.721954},
pmid = {42146614},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is a multifactorial disease with mixed pathologies. Consequentially, drugs targeting multiple pathological processes may offer synergistic benefits. While histone deacetylase (HDAC) inhibitors have demonstrated efficacy in alleviating AD-related pathologies in animal models, the neuroprotective Wnt/β-catenin signaling pathway remains compromised in AD brain. CI-994 is a class I HDAC inhibitor containing N-(2-aminophenyl)-benzamide. Our recent studies indicate that CI-994 is also an activator of Wnt/β-catenin signaling by stabilizing Wnt co-receptor LRP6. We herein use CI-994 as a scaffold to develop novel potent dual modulators of class I HDACs and Wnt/β-catenin signaling for AD therapy. Our lead compound, W2A-28, selectively inhibits class I HDAC1, 2 and 3 with IC 50 values of 0.51 μM, 0.68 μM, and 0.22 μM, respectively, and shows no inhibitory activities on other HDACs. Furthermore, W2A-28 potently activates Wnt reporter activity with an EC 50 value of 1.61 μM in Wnt-3A-expressing HEK293 cells. As expected, activation of Wnt/β-catenin signaling by W2A-28 is associated with elevated LRP6 protein level. Importantly, W2A-28 displays excellent microsomal stability in both mouse and human liver microsomal stability assays, alongside high permeability and a lack of active efflux in MDR1-MDCKII models. Critically, W2A-28 treatment significantly enhances histone acetylation, activates Wnt/β-catenin signaling, and suppresses tau phosphorylation in AD patient-specific cerebral organoids carrying APOE ε4/ε4 or APOE ε3/ε4 with PSEN1 M146V mutation. Our findings position W2A-28 as a promising multi-target drug candidate for AD therapy.},
}

@article {pmid42146852,
year = {2026},
author = {D'Amelio, C and Feroleto, C and Caligiuri, C and Li Puma, DD and De Chiara, G and Paoletti, I and Codazzi, C and D'Alelio, F and Miraglia, F and Pappalettera, C and Nucci, L and Frasca, F and Ventura, L and Manca, A and Morrone, M and Leone, L and Deriu, F and Morotti, M and Grassi, C and Vecchio, F and Podda, MV},
title = {EEG-motor correlation as early Alzheimer's disease index in herpes simplex virus type-1-infected mice.},
journal = {Brain communications},
volume = {8},
number = {3},
pages = {fcag128},
pmid = {42146852},
issn = {2632-1297},
abstract = {Alzheimer's disease is a neurodegenerative disorder characterized by cognitive decline and memory impairment. Early treatment requires reliable tests to identify the initial manifestations for developing treatments that modify disease progression. Neuroinflammation has been implicated as a key driver of the onset and progression of Alzheimer's disease. Herpes simplex virus type-1 (HSV-1), a neurotropic virus that establishes latency within the central nervous system, has been associated with increased proinflammatory cytokines, cognitive impairment and Alzheimer's disease-like pathology in human and rodent brains. This study employed a murine model showing an Alzheimer's disease-related phenotype, induced by HSV-1 infection and recurrent reactivation through thermal stress, to investigate previously unexplored motor function impairments and their correlation with EEG changes predictive of Alzheimer's disease-like pathology. Mice were subjected to two (2×TS) or seven thermal stress (7×TS) HSV-1 reactivations to reproduce mild and severe cognitive impairments, respectively, and were tested for recognition memory using the Novel Object Recognition test and for spatial memory using the Y-maze test. Motor performance was assessed using grip strength and grid walking tests. Local field potential recordings, immunohistochemical, morphological and molecular analyses were performed to characterize the effects of HSV-1 on neural circuits. 2×TS HSV-1 mice showed a reduced preference index in Novel Object Recognition compared to mice receiving mock infection (i.e. vehicle inoculum), whereas 7×TS HSV-1 mice displayed severe cognitive decline across the different memory domains. Motor function was preserved after the second thermal stress but was impaired after the seventh thermal stress, with reduced forelimb force and increased foot faults starting from the fourth reactivation. Following the seventh reactivation, HSV-1 mice showed astrogliosis and phosphorylated Tau accumulation. In vivo, electrophysiological recordings revealed increased functional connectivity across frequency bands in 2×TS HSV-1 mice compared to controls, with negative correlations between total coherence and grip strength. Increased spine density in the frontal cortex of 2×TS HSV-1 mice supports early neuronal network alterations. From a translational perspective, we preliminarily evaluated comparable motor indices in healthy human participants, in patients with mild cognitive impairment, and in patients with Alzheimer's disease. As expected, both grip strength and dynamic balance were lower in patients with Alzheimer's disease compared to healthy and mild cognitive impairment subjects. Notably, grip strength was significantly reduced in mild cognitive impairment subjects, who displayed early motor impairment. Our findings highlight the potential of EEG-based biomarkers for early Alzheimer's disease detection and suggest motor indices as novel prognostic markers.},
}

@article {pmid42146883,
year = {2026},
author = {García-Alberca, JM and Mendoza, S and DE LA Guía, P and López DE LA Rica, M},
title = {Effectiveness of Souvenaid® combined with acetylcholinesterase inhibitors on caregiver burden in Alzheimer´s disease.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {},
pages = {e70262},
pmid = {42146883},
issn = {2352-8737},
abstract = {INTRODUCTION: The burden experienced by caregivers of Alzheimer´s disease (AD) patients is a complex and stressful situation influenced by distinct variables, such as the patient´s need for monitoring, social isolation, mental or physical health problems, or financial challenges. In additon, behavioral and psychological symptoms of dementia are strongly associated with caregiver experiences of burden.

METHODS: This was a 12-month, retrospective, single-center, real-world study to evaluate the effectiveness of the combined treatment with Souvenaid and acetylcholinesterase inhibitors (AChEI) compared to treatment with either AChEI alone or Souvenaid alone on caregiver burden, anxiety and depression in patients, and AD patients attending a memory clinic. Assessments were conducted using the Zarit Burden Interview (ZBI), the Beck Depression Inventory (BDI), the State Trait Anxiety Inventory-State (STAI-S), and the Neuropsychiatric Inventory-Caregiver distress scale (NPI-D). A mixed model for repeated measures was conducted to evaluate differences from baseline to month 12 between caregivers in the three treatment groups.

RESULTS: At 12 months, caregiver burden, depression, anxiety levels, and the emotional distress in the context of behavioral and psychological symptoms of dementia (BPSD) improved in caregivers in the Souvenaid plus AChEI group (n = 70) compared to those in the AChEI group (n = 84) and those in the Souvenaid group (n = 66).The mean change for the ZBI score was found to be significantly higher in the Souvenaid plus AChEI group than in the AChEI group (p < 0.001) and the Souvenaid group (p < 0.001). In addition, there was a significant difference in the mean change for the BDI, STAI-S, and NPI-D scores between groups, favoring the Souvenaid plus AChEI group over the AChEI and Souvenaid groups.

DISCUSSION: In addition to assessing patients' cognitive, behavioral, and daily functioning, it is recommended regular monitoring of caregiver burden while providing support for patients with dementia. The combined treatment with Souvenaid and AChEI may have a significant impact on caregivers' experience of burden.},
}

@article {pmid42147211,
year = {2024},
author = {Prinz, A and Buerger, D and Krafft, J and Bergmann, M and Woll, A and Barisch-Fritz, B and Witte, K},
title = {Use of Immersive Virtual Reality in Nursing Homes for People With Dementia: Feasibility Study to Assess Cognitive, Motor, and Emotional Responses.},
journal = {JMIR XR and spatial computing},
volume = {1},
number = {},
pages = {e54724},
pmid = {42147211},
issn = {2818-3045},
abstract = {BACKGROUND: Physical activity interventions for people with dementia have shown promising effects in improving cognition and physical function or slowing disease-related decline. Immersive virtual reality (iVR), using head-mounted displays, facilitates realistic experiences by blurring the boundaries between VR and the real world. The use of iVR for people with dementia offers the potential to increase active time and improve dementia therapy and care through exercise interventions. However, the feasibility of using VR use in people with dementia, considering changes in motor, cognitive, psychological, and physiological parameters, remains insufficiently investigated.

OBJECTIVE: This study aims to investigate the feasibility of using iVR in people with dementia or mild cognitive impairment in nursing homes. Specifically, we examined changes in motor performance (balance and mobility), cognitive performance (global cognition and executive functions), emotional responses, and fear of falling using iVR.

METHODS: Utilizing a pre-post design, this study recruited 35 participants with mild-to-moderate dementia, assessed by the Mini-Mental State Examination (MMSE). Participants underwent a single session involving iVR exposure, with pre- and postexposure assessments and a feedback form, to exclude negative effects on cognitive and motor functions, mood, anxiety levels, and balance performance. The use of iVR involved 4 scenes, with a total length of 8 minutes. These scenes depicted a park with short and rather passive impressions presented as a 360° video in a head-mounted display. Before and after using the iVR, cognitive parameters were assessed using the Trail-Making Test A (TMT-A), motor parameters were assessed using the FICSIT-4 (Frailty and Injuries: Cooperative Studies of Intervention Techniques-4) and Timed-Up-and-Go (TUG) tests, and psychological parameters were assessed using the Dementia Mood Picture Test, State-Trait Anxiety Inventory, and Short Falls Efficacy Scale-International (Short FES-I). The Emotion Rating Scale and the duration of use were recorded during use, and a feedback questionnaire was completed afterward in addition to the posttests. Paired t tests and Wilcoxon tests were used to examine pre-post differences.

RESULTS: Of the 35 initial participants, 33 completed the study, which corresponds to a dropout rate of 6%. All 33 participants, who had a mean of 83.71 (SD 5.01) years, had dementia. They showed no statistically significant difference in cognitive and motor performance before and after iVR use. Thus, no negative effects on cognitive and motor functions, mood, anxiety levels, and balance performance were observed. The emotion rating scale also showed that 72% (n=24) felt joy and fun during iVR use, 100% (n=33) showed no emotions such as fear, sadness, or anger, and 93% (n=31) were attentive during iVR use.

CONCLUSIONS: The feasibility of using iVR for people with dementia can be rated positively. There were no changes in motor, cognitive, or emotional parameters that would increase the risk of falls or other negative emotional reactions during or after iVR use. Further studies are needed to investigate prolonged use in a more stimulating computer-generated environment and possible physical and cognitive tasks for people with dementia in nursing homes.

TRIAL REGISTRATION: German Clinical Trials Register DRKS00030616; https://drks.de/search/de/trial/DRKS00030616.},
}

@article {pmid42147344,
year = {2026},
author = {Geerts, H and Short, SM and Grant, A and van der Graaf, PH},
title = {Understanding quantitative effects of anti-amyloid therapies on tau biomarkers and functional outcome. Insights from a comprehensive mechanistic quantitative systems pharmacology study.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1813290},
pmid = {42147344},
issn = {1663-9812},
abstract = {INTRODUCTION: Anti-amyloid antibodies have the potential to become the standard of care in Alzheimer's Disease (AD) and large datasets from clinical trials allow the testing of predictive models on fluid biomarkers and functional outcomes. However, identifying an easily accessible biomarker to determine the time to switch to maintenance therapy, and identifying patient profiles with optimal cognitive benefit, are still unresolved issues in clinical practice.

METHODS: Predicted changes in monomers, oligomers, protofibrils and plaques were simulated using a well-validated Quantitative Systems Pharmacology model based on biophysical and biological assumptions of amyloid synthesis, aggregation and clearance. This model was combined with a previously calibrated computational neuronal network model of cognitive outcome in AD patients by introducing the effect of amyloid and tau oligomers on specific voltage- and ligand-gated ion channels, informed by preclinical studies.

RESULTS: The model accounted for 70% and 50% of the variance of clinically observed changes in plasma p-tau181 and Clinical Dementia Rating-Sum Of Boxes (CDR-SOB) respectively, in clinical trials of seven amyloid antibodies. We derived an antibody specific normalized decrease of plasma p-tau181 (-15% for donanemab, -45% for aducanumab and -75% for lecanemab) to determine trial duration for achieving central amyloid negativity. Using the concept of information processing bandwidth, the model suggests that anti-amyloid antibodies slow the cognitive worsening compared to placebo while at the same time lowering plasma p-tau181 levels by reducing neuronal firing. Finally, the model suggests that independently from the degree of amyloid reduction, the beneficial cognitive effect of treatment decreases with more advanced neuronal pathology and higher baseline tau-load. This provides a hypothesis for the impact of disease pathology and gender effect on functional outcomes with lecanemab and gantenerumab.

DISCUSSION: With further validation, this model has the capability to support optimization of clinical trial design for amyloid-tau combination therapy.},
}

@article {pmid42147618,
year = {2026},
author = {Sewell, DD and Kallenberg, G and Mandel, B and Mandvi, A and Asmus, L and Neel, IC and Heimler, G and Andrew, W and Lobatz, M},
title = {Enhancing Dementia Care in Primary Care: Impact of Targeted Training and Electronic Medical Record (EMR)-Integrated Algorithms.},
journal = {Cureus},
volume = {18},
number = {4},
pages = {e107031},
pmid = {42147618},
issn = {2168-8184},
abstract = {INTRODUCTION: The number of medical specialists whose training programs provide robust education in dementia diagnosis and treatment pales in comparison to the increasing number of individuals living with dementia. Primary care providers (PCPs) care for most older adults with cognitive concerns and dementia. Summarized here are the results of an effort to help PCPs care for these patients using targeted training and electronic medical record (EMR)-integrated clinical algorithms.

METHODS: Clinicians from two University of California San Diego Family Medicine Clinics completed assessments of dementia knowledge and comfort in caring for patients and family members impacted by dementia four times: enrollment, and approximately two, nine and 15 months after a three-component intervention: 1) training via four online educational modules (six hours total) on screening, evaluation, and care of patients with dementia; 2) integration of clinical algorithms into the EMR system and 3) access to mentoring from a more experienced peer.

RESULTS: Subjective assessment of comfort and competence of intervention group clinicians in working with patients with cognitive complaints significantly increased and was higher for intervention group PCPs than the comparison group PCPs. Evidence of completed AD8s (Eight-Item Informant Interview to Differentiate Aging and Dementia) at both clinics increased from baseline to post-intervention: 52.85% to 82.6% and 66.1% to 86.9%.

DISCUSSION: Training PCPs on dementia screening and diagnosis, and integration of algorithms into the EMR, improved clinician subjective competence and comfort in caring for patients with cognitive complaints and increased the AD8 completion rate. The small number of study participants mandates caution when interpreting these findings.},
}

@article {pmid42148080,
year = {2026},
author = {You, J and Liu, Q and Li, X},
title = {Anti-Aβ3-10 monoclonal antibody 7B8 improves cognitive function and protects the blood-brain barrier in APP/PS1 mice by regulating the HMGB-1/RAGE/NF-κB pathway.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1781351},
pmid = {42148080},
issn = {1664-3224},
mesh = {Animals ; *Blood-Brain Barrier/drug effects/metabolism/immunology ; Mice ; Mice, Transgenic ; *Amyloid beta-Peptides/immunology/antagonists & inhibitors ; *Alzheimer Disease/metabolism/drug therapy/immunology ; *Cognition/drug effects ; Amyloid beta-Protein Precursor/genetics ; NF-kappa B/metabolism ; Signal Transduction/drug effects ; HMGB1 Protein/metabolism ; Disease Models, Animal ; *Antibodies, Monoclonal/pharmacology ; Presenilin-1/genetics ; Receptor for Advanced Glycation End Products/metabolism ; Male ; Mice, Inbred C57BL ; Humans ; *Peptide Fragments/immunology ; },
abstract = {BACKGROUND: Alzheimer's disease (AD), the most prevalent dementia, is primarily underpinned by the amyloid cascade hypothesis. Passive Aβ immunotherapy effectively reduces cerebral Aβ deposition but is limited by severe side effects, including cerebral amyloid angiopathy (CAA), microhemorrhage, and amyloid-related imaging abnormalities (ARIA). Here, we investigated the efficacy and safety of a novel anti-A3-10 monoclonal antibody (7B8) in APP/PS1 double-transgenic mice, with a focus on its impacts on amyloid clearance, neuroinflammation, and blood-brain barrier (BBB) integrity.

METHODS: 7B8 was generated by immunizing mice with A3-10-KLH. Six-month-old APP/PS1 mice were intraperitoneally injected with 7B8 (10 mg/kg) weekly for 8 doses (7B8 group). Age-matched APP/PS1 mice treated with IgG and C57BL/6J mice served as negative and wild-type (WT) controls, respectively. One week after the final injection, behavioral tests were performed, followed by euthanasia for histological (left brain hemisphere) and biochemical (right brain hemisphere) analyses.

RESULTS: Compared with the IgG group, the 7B8 group exhibited significantly reduced cerebral Aβ deposition and improved cognitive function (both P < 0.05), comparable to the WT group. Notably, in these young 6-month-old APP/PS1 mice with early-stage amyloid deposition and minimal CAA pathology, 7B8 treatment did not increase microhemorrhage risk relative to the IgG control group (P > 0.05). Furthermore, 7B8 preserved vascular integrity by reducing perivascular Aβ40 deposition and smooth muscle actin damage, while enhancing endothelial cell fluorescence intensity (P < 0.05). At the molecular level, 7B8 upregulated vascular LRP-1 and BBB tight junction proteins (ZO-1, CLDN-5, Occludin), and downregulated RAGE expression (P < 0.05). It also suppressed microglial and astrocytic activation, reduced levels of IL-6 and cortical TNF-α, and inhibited the HMGB-1/RAGE/NF-κB signaling pathway (P < 0.05), without affecting global TNF-α or IL-1β levels.

CONCLUSION: 7B8 effectively alleviates cognitive impairment and clears cerebral and perivascular amyloid deposits in young APP/PS1 mice with early-stage AD pathology and minimal CAA, with no increased risk of microhemorrhage in this experimental setting. It also protects vascular structure and BBB integrity by inhibiting the HMGB-1/RAGE/NF-κB-mediated neuroinflammatory response. Given the limitations of evaluating CAA-related safety in young mice, future studies using mid-aged (12-15-month-old) APP/PS1 mice with prominent CAA will be conducted to fully characterize 7B8's safety profile. These findings highlight 7B8 as a promising candidate for safe and effective AD immunotherapy, providing new insights into the development of ARIA-minimizing strategies.},
}

Animals
*Blood-Brain Barrier/drug effects/metabolism/immunology
Mice
Mice, Transgenic
*Amyloid beta-Peptides/immunology/antagonists & inhibitors
*Alzheimer Disease/metabolism/drug therapy/immunology
*Cognition/drug effects
Amyloid beta-Protein Precursor/genetics
NF-kappa B/metabolism
Signal Transduction/drug effects
HMGB1 Protein/metabolism
Disease Models, Animal
*Antibodies, Monoclonal/pharmacology
Presenilin-1/genetics
Receptor for Advanced Glycation End Products/metabolism
Male
Mice, Inbred C57BL
Humans
*Peptide Fragments/immunology

@article {pmid42148242,
year = {2025},
author = {Khazaneha, M and Khadir, E and Motaghi, N and Arvan, H and Ebrahimi-Meimand, HA},
title = {Scientometric insights into neurology publications in Iran.},
journal = {Current journal of neurology},
volume = {24},
number = {1},
pages = {87-96},
pmid = {42148242},
issn = {2717-011X},
abstract = {Background: Undoubtedly, medical science has been born since the beginning of human creation. One of its important branches is neurology. Neurosciences in Iran, with a little delay from the first world, with the efforts of researchers, opened the way for the diagnosis and treatment of neurological diseases, and we reached the place where we are. Methods: In this bibliometric and scientometric study, we have evaluated the process of neurological science in Iran. By referring to the reliable indexes, we checked Web of Science (WoS), PubMed, and Scopus from 1963 onwards. We showed the published activities of Iranians in the form of charts and tables. Results: This study indicates the increasing growth of scientific studies in the field of neurology. In the field of neuroscience, the researchers are mostly aimed at the education and training of specialists and PhD students, and depending on the research facilities, as well as acquaintances and connections for the publication of articles. Diseases that have afflicted a large number of people causing them to suffer and limiting their activities, such as multiple sclerosis (MS), Alzheimer's, epilepsy, Parkinson's, and brain strokes have been the focus of researchers. Conclusion: Neurological studies have an increasing trend and can be divided into two basic sections, which are mainly done by neuroscientists and are based on the educational needs and training of specialists, but neurology studies and scientific publications are mainly done by neurologists and based on feeling the need and diseases in this field have been done.},
}

@article {pmid42148368,
year = {2026},
author = {Bailey-Taylor, MJ and Morrow, P and Hendrix, J and Galluzzi, KE and Sharafsaleh, G},
title = {Therapeutic Landscape of Early Symptomatic Alzheimer's Disease Translated into Everyday Practice for Geriatric Providers.},
journal = {Clinical interventions in aging},
volume = {21},
number = {},
pages = {585263},
pmid = {42148368},
issn = {1178-1998},
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnosis ; Aged ; Cognitive Dysfunction/drug therapy ; Disease Progression ; Biomarkers ; },
abstract = {Alzheimer's disease (AD) accounts for 60-80% of all dementia cases. Recent advances in diagnostic biomarkers of early symptomatic AD (ie, mild cognitive impairment and mild dementia due to AD) and amyloid-targeting therapies (ATTs) have the potential to improve outcomes for patients with AD. Two ATTs (donanemab and lecanemab) are currently approved and available for use in the US. Both ATTs can slow disease progression as well as cognitive and functional decline in patients with early symptomatic AD. Treatment with ATTs is associated with specific safety concerns such as amyloid-related imaging abnormalities. Therefore, the benefit versus risk profile needs to be carefully considered when deciding whether to treat a patient with ATTs. This review aims to educate geriatric-trained health professionals regarding advances in the diagnosis and treatment of early symptomatic AD, including the optimal duration of treatment, management of adverse reactions, and patient counseling. It also discusses key considerations in care transitions and patient management in multidisciplinary settings to ensure continuous patient-centered care.},
}

Humans
*Alzheimer Disease/drug therapy/diagnosis
Aged
Cognitive Dysfunction/drug therapy
Disease Progression
Biomarkers

@article {pmid42148603,
year = {2026},
author = {Xu, Q and Lu, J and Zhang, Z and Xu, D and Guo, C},
title = {Deep learning-based cognitive impairment brain imaging analysis: New methods, new technologies, and new paradigms.},
journal = {Neural regeneration research},
volume = {21},
number = {9},
pages = {4135-4147},
doi = {10.4103/NRR.NRR-D-25-00332},
pmid = {42148603},
issn = {1673-5374},
abstract = {Cognitive impairment arising from ischemic stroke, Alzheimer's disease, and Parkinson's disease presents distinct structural and network-level alterations. Brain magnetic resonance imaging offers a non-invasive and high-resolution approach to assess these changes, while deep learning provides powerful tools for automated analysis. Given that accurate lesion delineation, precise localization of abnormal regions, and reliable disease classification are fundamental to clinical decision-making. This review aims to explore the application of deep learning techniques to brain magnetic resonance imaging analysis of cognitive impairments caused by these disorders, with a focus on three core tasks: lesion segmentation, object detection, and image classification. Recent widely accepted findings indicate that ischemic stroke studies have achieved state-of-the-art lesion segmentation performance, with optimized U-shaped convolutional network (U-Net) and hybrid convolutional neural network-transformer models reaching Dice scores up to 0.911 in delineating focal damage. Alzheimer's disease research has advanced classification and staging accuracy by more than 10% compared with unimodal baselines through three-dimensional convolutional neural network, Transformers, and multimodal fusion, enabling more precise detection of diffuse cortical atrophy. Parkinson's disease imaging, despite lacking overt structural lesions, has leveraged ResNet and Vision Transformer backbones to identify subtle and spatially distributed abnormalities, improving early-stage differentiation. Persistent challenges include the scarcity of large, high-quality annotated datasets, substantial inter-site variability, high annotation costs, and limited interpretability, hindering clinical integration. Addressing these barriers will require advances in federated learning to mitigate data scarcity while preserving privacy, domain adaptation techniques to reduce inter-site variability, automated annotation, and low-resource training strategies to lower labeling costs, and explainable artificial intelligence to improve interpretability, thereby ensuring model robustness, privacy, and transparency. This review highlights emerging methods, innovative technologies, and novel paradigms that are redefining brain imaging analysis in cognitive impairment. Mechanistically, deep learning improves cognitive impairment analysis by integrating hierarchical and multiscale spatial features, modeling long-range functional connectivity disruptions, and fusing structural with functional imaging to better represent network-level pathology. In conclusion, aligning network architectures with disease-specific imaging characteristics and task requirements can greatly enhance the accuracy, robustness, and generalizability of magnetic resonance imaging analyses for cognitive impairment. Future work should focus on multimodal fusion, structure-function coupling, cross-disease evaluations, and embedding artificial intelligence tools into clinical workflows to support early detection, individualized treatment planning, and large-scale clinical adoption.},
}

@article {pmid42138018,
year = {2026},
author = {Chen, CP and Zhang, T and E, ED and Xu, TY and Han, Q and Gao, X and Sun, J and Huang, Y and Yang, JH and Zhang, XQ},
title = {Targeting mGluR2/3 Signaling With LY341495 Restores Dentate Gyrus Function and Cognitive Performance in a Male Mouse Model of Alzheimer's Disease.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {5},
pages = {e70916},
pmid = {42138018},
issn = {1755-5949},
support = {82201322//National Natural Science Foundation of China/ ; LY24H090001//the Natural Science Foundation of Zhejiang Province/ ; 2024010317//Ningbo Top Medical and Health Research Program/ ; 2022020304//Ningbo Top Medical and Health Research Program/ ; 2023H017//Ningbo Science and Technology Project/ ; 2024L003//Ningbo Clinical Research Center for Emergency and Critical Diseases/ ; },
mesh = {Animals ; Male ; *Alzheimer Disease/drug therapy/pathology/genetics/metabolism/psychology ; *Receptors, Metabotropic Glutamate/antagonists & inhibitors/metabolism ; *Dentate Gyrus/drug effects/metabolism ; Mice, Transgenic ; Mice ; Disease Models, Animal ; *Xanthenes/pharmacology/therapeutic use ; *Amino Acids/pharmacology/therapeutic use ; *Cognition/drug effects ; Signal Transduction/drug effects ; Amyloid beta-Protein Precursor/genetics ; Presenilin-1/genetics ; Mice, Inbred C57BL ; },
abstract = {BACKGROUND: Aberrant metabotropic glutamate receptor 2/3 (mGluR2/3) signaling has been implicated in the synaptic and cognitive deficits observed in Alzheimer's disease (AD), yet the underlying regulatory mechanisms remain unclear. This study investigated the therapeutic potential of LY341495, a selective mGluR2/3 antagonist, in APP/PS1 transgenic mice, a widely used AD model.

METHODS: Male APP/PS1 mice were treated with the selective mGluR2/3 antagonist LY341495. Cognitive performance was evaluated using behavioral tests. Hippocampal dentate gyrus (DG) alterations were examined by immunohistochemistry and electrophysiology, including analyses of mGluR2/3 expression, excitatory synaptic activity, adult neurogenesis, calbindin expression, and amyloid-β plaque burden.

RESULTS: APP/PS1 mice exhibited pathological upregulation of mGluR2/3 in the DG, accompanied by altered presynaptic glutamatergic transmission, reduced neurogenesis, decreased calbindin expression, and deficits in recognition and spatial memory. LY341495 treatment attenuated the aberrant mGluR2/3 upregulation, enhanced excitatory synaptic activity, and improved calbindin levels and neurogenesis in the DG. Importantly, these changes were associated with significant reductions in DG amyloid-β plaque burden and marked improvements in cognitive performance.

CONCLUSIONS: This study highlights the novelty of linking mGluR2/3 inhibition to the restoration of calcium-buffering capacity, as reflected by calbindin expression and neurogenesis, processes critical for DG plasticity and resilience. These findings underscore the therapeutic potential of LY341495 as a novel intervention targeting mGluR2/3 signaling in AD.},
}

Animals
Male
*Alzheimer Disease/drug therapy/pathology/genetics/metabolism/psychology
*Receptors, Metabotropic Glutamate/antagonists & inhibitors/metabolism
*Dentate Gyrus/drug effects/metabolism
Mice, Transgenic
Mice
Disease Models, Animal
*Xanthenes/pharmacology/therapeutic use
*Amino Acids/pharmacology/therapeutic use
*Cognition/drug effects
Signal Transduction/drug effects
Amyloid beta-Protein Precursor/genetics
Presenilin-1/genetics
Mice, Inbred C57BL

@article {pmid42139159,
year = {2026},
author = {Carvalho, MS and Barssotti, L and Santos, LMBD and Rosa, LRO and Gomes-Marcondes, MCC and Carneiro, EM and Barbosa, HCL and Zangerolamo, L},
title = {Tauroursodeoxycholic acid (TUDCA) ameliorates age-related skeletal muscle loss.},
journal = {The Journal of physiology},
volume = {},
number = {},
pages = {},
doi = {10.1113/JP290683},
pmid = {42139159},
issn = {1469-7793},
support = {2021/13917-6//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; },
abstract = {Ageing leads to changes in body composition, including increased adiposity and reduced skeletal muscle mass and force. The alterations in ageing skeletal muscle result from impaired proteostasis driven by factors such as chronic inflammation, hormonal changes and reduced nutrient absorption. Those age-related changes in body composition and skeletal muscle compromise mobility and increase the risk of falls, fractures and metabolic disorders. Tauroursodeoxycholic acid (TUDCA), a bile acid with known benefits in chronic diseases, has been shown by our group to improve cognition and metabolic homeostasis in ageing and Alzheimer's disease mouse models. Interestingly, in previous studies, TUDCA treatment was also associated with increased skeletal muscle mass in ageing mice, leading us to hypothesize that TUDCA could target skeletal muscle to reduce age-related muscle loss. To explore this, we treated 18-month-old C57BL/6 mice with TUDCA or vehicle for 20 days, using 3-month-old mice as a young control group. We demonstrate that TUDCA treatment decreases body weight while increasing skeletal muscle mass, restores muscle fibre size and preserves functional integrity. Additionally, TUDCA enhances skeletal muscle insulin sensitivity through increased AKT activation and reduces tissue inflammation. Such improvements collectively support the restoration of skeletal muscle proteostasis, as indicated by increased protein synthesis and phosphorylation of key anabolic signalling pathways, including ribosomal protein S6 kinase beta-1 (P70S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1). These findings contribute to a better understanding of TUDCA's actions on skeletal muscles of ageing mice and highlight its role as a promising strategy against age-related muscle loss. KEY POINTS: Tauroursodeoxycholic acid (TUDCA) treatment attenuates skeletal muscle loss in ageing mice. TUDCA improves skeletal muscle insulin sensitivity and restores AKT signalling. TUDCA exerts an anti-inflammatory effect in skeletal muscle of ageing mice. TUDCA emerges as a potential therapy for age-related skeletal muscle loss.},
}

@article {pmid42139977,
year = {2026},
author = {Soni, U and Pujari, R},
title = {Gentisic acid confers multimodal neuroprotection in experimental Alzheimer's disease by targeting oxidative stress, neuroinflammation, and protein aggregation.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {156},
number = {},
pages = {158276},
doi = {10.1016/j.phymed.2026.158276},
pmid = {42139977},
issn = {1618-095X},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline associated with oxidative stress, neuroinflammation, cholinergic dysfunction, and accumulation of amyloid-β (Aβ) and hyperphosphorylated tau (p-tau). Given the multifactorial nature of AD, phytochemicals with multi-target pharmacological properties are of growing therapeutic interest. Gentisic acid (GA; 2,5-dihydroxybenzoic acid) possesses established antioxidant and anti-inflammatory activities; however, its potential relevance in AD has not been comprehensively evaluated.

PURPOSE: This study investigated the neuroprotective potential of gentisic acid against Alzheimer-like pathology using integrated in vitro and in vivo experimental models.

STUDY DESIGN: A preclinical experimental study combining cell-based assays and an aluminium chloride (AlCl3) and D-galactose (D-Gal)-induced rat model of AD-like neurodegeneration was conducted.

METHODS: Blood-brain barrier (BBB) permeability of GA was assessed using a PAMPA-BBB assay. Neuroprotective effects were examined in AlCl₃-exposed SH-SY5Y cells. In vivo, Wistar rats received AlCl₃ and D-Gal to induce cognitive and biochemical alterations, followed by oral GA treatment. Behavioral paradigms such as open field, Morris water maze, novel object recognition, elevated plus maze and Y-maze tests were employed to assess spatial learning, recognition memory, and anxiety-like behavior. Oxidative stress markers, antioxidant enzymes, acetylcholinesterase activity, monoaminergic neurotransmitters, brain-derived neurotrophic factor (BDNF), pro-inflammatory cytokines, amyloid beta, and hyperphosphorylated tau protein levels were quantified. Histopathological evaluation of hippocampal and cortical regions was performed.

RESULTS: GA demonstrated adequate BBB permeability and concentration-dependent protection against AlCl₃-induced cytotoxicity in SH-SY5Y cells. In the rat model, GA (10, 30, and 100 mg/kg, per oral (p.o.) improved cognitive performance and attenuated anxiety-like behavior. Treatment with GA reduced lipid peroxidation (malondialdehyde), restored antioxidant defenses (superoxide dismutase, catalase and reduced glutathione), inhibited acetylcholinesterase activity, and normalized monoaminergic neurotransmitters (serotonin and dopamine). GA further elevated BDNF levels and suppressed pro-inflammatory cytokines (tumor necrosis factor-alpha and interleukin-1 beta). Notably, GA decreased cerebral Aβ and p-tau accumulation and preserved hippocampal and cortical architecture.

CONCLUSION: Gentisic acid exerts multi-modal neuroprotective effects, including antioxidant, anti-inflammatory, anti-cholinesterase, and anti-amyloidogenic actions, in experimental models of AD. These findings support its potential as a phytochemical candidate for further development in the prevention or adjunctive management of AD.},
}

@article {pmid42141012,
year = {2026},
author = {Gorin, BI and Pozdnyakov, SO and Potapova, KA and Tukhovskaya, EA and Gorchakov, DS},
title = {Efficacy and safety of DMB-I (latrepirdine) therapy in mild to moderate dementia in Alzheimer's disease: results of a multicenter, double-blind, randomized, placebo-controlled, clinical trial in three parallel groups.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42141012},
issn = {2045-2322},
abstract = {Alzheimer’s disease (AD) is one of leading dementia causes, affecting over 50 million people worldwide. A multicenter, double-blind, randomized, placebo-controlled clinical trial in three parallel groups was conducted to evaluate efficacy and safety of Latrepirdine polymorph DMB-I in 26-week treatment of dementia in patients with AD. 135 patients of both sexes aged 60 to 90 years were randomized into three groups: DMB-I + placebo, 30 mg/day; DMB-I, 60 mg/day and Placebo. Treatment efficacy was assessed using Alzheimer’s disease Assessment Scale cognitive subscale (ADAS-cog), Mini-Mental State Examination (MMSE-2), quality of life questionnaire (QOL-AD), Clinical Global Impression scale (CGI) and Instrumental Activities of Daily Living score (IADL). Clinical parameters and adverse events (AEs) also assessed. The efficacy of DMB-I at a dose of 60 mg/day was demonstrated by assessing the primary efficacy criterion, namely, a significant change in the ADAS-cog score after 26 weeks of treatment compared with baseline. Severity of cognitive impairment dynamics on ADAS-cog, CGI and LADL scales was significantly improved in groups receiving DMB-I at both doses, compared with placebo. AEs overall incidence was similar between DMB-I and Placebo groups. 26-week therapy with DMB-I at both doses demonstrated efficacy and favorable safety profile. 60 mg/day dose was selected as optimal dose for further studies. Study retrospectively registered on Clinicaltrials.gov on February 27, 2024, NCT06292351.},
}

@article {pmid42141074,
year = {2026},
author = {Cai, C and Chong, YS and Liang, H and Hu, Y and Hu, Q and Chen, J and Sajikumar, S and Liu, F},
title = {Simvastatin rescues cognitive impairment in an Aβ1-42-induced model of Alzheimer's disease through the HDAC2-BDNF signaling pathway.},
journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42141074},
issn = {1740-634X},
support = {2021J011433//Natural Science Foundation of Fujian Province (Fujian Provincial Natural Science Foundation)/ ; 82201668//National Natural Science Foundation of China (National Science Foundation of China)/ ; MOH-000641-00//MOH | National Medical Research Council (NMRC)/ ; MOH-001883-00//MOH | National Medical Research Council (NMRC)/ ; },
abstract = {Statins, renowned for their efficacy in treating cardiovascular diseases, have emerged as potential therapeutic agents for the prevention of Alzheimer's disease (AD). Among them, simvastatin (SV) has attracted considerable attention for its reported cognitive benefits in AD. However, the precise mechanisms by which SV modulates spatial cognitive function in AD remain unclear. In the present study, we used an AD model induced through intracerebroventricular administration of Aβ1-42 in male C57BL/6 mice. The cognitive performance were assessed using the Morris Water Maze (MWM) test, the Y-maze and the Novel Object Recognition (NOR) test. HDAC2 and BDNF expression levels were analyzed by Western blotting. Chromatin immunoprecipitation (ChIP) assays were performed to examine histone H4 acetylation (Ac-H4K5) at Bdnf promoters. Our results showed that SV treatment reversed cognitive impairments induced by Aβ1-42. Aβ1-42 administration increased HDAC2 expression, reduced histone H4 acetylation, and decreased BDNF levels in the dorsal hippocampus (dHPC), all of which were restored by SV treatment. Notably, viral overexpression of HDAC2 abolished the beneficial effects of SV, underscoring the critical role of HDAC2 in mediating its actions. Furthermore, blockade of BDNF signaling using TrkB-Fc attenuated the behavioral improvements induced by SV. In addition, SV treatment ameliorated Aβ1-42-induced deficits in neurogenesis and long-term potentiation (LTP). Together, these findings highlight the therapeutic role of SV in AD through epigenetic and synaptic mechanisms, and support further investigation into its clinical applicability.},
}

@article {pmid42141084,
year = {2026},
author = {Shahat, EA and Ayoub, IM and Bakr, RO and Gad, HA and Eldahshan, OA and Singab, ANB},
title = {Comparative analysis of volatile composition and anticholinesterase activity of Egyptian Hedychium coronarium and Alpinia zerumbet using chemometric assessment of extraction techniques.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42141084},
issn = {2045-2322},
mesh = {*Zingiberaceae/chemistry ; *Alpinia/chemistry ; *Oils, Volatile/chemistry/pharmacology/analysis/isolation & purification ; *Cholinesterase Inhibitors/pharmacology/chemistry/isolation & purification ; Plant Leaves/chemistry ; Gas Chromatography-Mass Spectrometry ; Rhizome/chemistry ; *Plant Extracts/chemistry/pharmacology ; Antioxidants/pharmacology/chemistry ; Chemometrics ; Egypt ; },
abstract = {Hedychium coronarium and Alpinia zerumbet are rhizomatous plants belonging to the family Zingiberaceae. They are rich in essential oils. Hydrodistillation and headspace (HS) were employed for the extraction of the essential oils from the leaves and rhizomes of both plants. Essential oils were then analysed by GC/MS and the obtained results were subjected to chemometric analysis. The oil samples obtained by hydrodistillation were tested for their antioxidant and anti-cholinesterase activities using oxygen radical antioxidant capacity assay and colorimetric inhibition kit, respectively. Hydro-distilled oil from H. coronarium leaves showed the presence of forty-seven compounds (97.73%) compared to sixteen compounds (99.17%) in the HS volatiles. Meanwhile, hydro-distilled oil from H. coronarium rhizomes showed the presence of thirty-nine components (95.84%) compared to fifteen compounds (98.68%) in the HS volatiles with 1,8-cineole (41.69% and 58.41%) as the major component in both samples. A. zerumbet leaves oil showed the presence of nineteen compounds (94.54%) in the hydrodistilled oil and twenty-one compounds (99.53%) in the HS volatiles. Besides, the rhizomes hydrodistilled essential oil showed twenty-three compounds (91.85%) and sixteen compounds (100%) in the HS with 1,8-cineole (20.78% and 23.63%) representing the major component in both samples. Chemometric analysis of the results provided a clear and statistically robust discrimination between the hydrodistilled and headspace-isolated oil samples demonstrating that extraction method is a primary determinant of volatile profile. Principal component analysis score plot explained 75% of total variance and distinctly separated samples into four main clusters with key discriminating components β-pinene, and caryophyllene were the major responsible for the segregation of H. coronarium leaves by headspace and hydrodistillation extraction methods, respectively, besides, 1,8-cineole accounted for the discrimination of H. coronarium rhizomes extracted by hydrodistillation. Hierarchial cluster analysis (HCA) fully supported this classification, confirming consistent grouping patterns across both analyses. Importantly, A. zerumbet oils from both extraction methods clustered closely, indicating compositional stability, whereas H. coronarium samples showed strong method-dependent divergence. A. zerumbet rhizomes oil showed the strongest activity as anticholinesterase with IC50 of 0.54 ± 0.02 µg/mL while H. coronarium rhizomes showed the strongest antioxidant activity (10.06 ± 0.16 TE µM/L). H. coronarium leaves and A. zerumbet rhizomes showed anticholinesterase and antioxidant activities to such an extent that may make them a useful adjuvant in the treatment of cognitive diseases such as Alzheimer's.},
}

*Zingiberaceae/chemistry
*Alpinia/chemistry
*Oils, Volatile/chemistry/pharmacology/analysis/isolation & purification
*Cholinesterase Inhibitors/pharmacology/chemistry/isolation & purification
Plant Leaves/chemistry
Gas Chromatography-Mass Spectrometry
Rhizome/chemistry
*Plant Extracts/chemistry/pharmacology
Antioxidants/pharmacology/chemistry
Chemometrics
Egypt

@article {pmid42142416,
year = {2026},
author = {Chiba, Y and Ide, K and Suzuki, S and Taguri, M and Suzuki, H and Abe, K and Yoshimi, A and Okuda, T and Saito, K and Mizushima, S and Yamanaka, T and Hishimoto, A and Sakurai, T and Arai, H and Asami, T and Odawara, T},
title = {Multimodal intervention benefits: Responder analysis of J-MINT PRIME Kanagawa trial.},
journal = {Archives of gerontology and geriatrics},
volume = {149},
number = {},
pages = {106289},
doi = {10.1016/j.archger.2026.106289},
pmid = {42142416},
issn = {1872-6976},
abstract = {INTRODUCTION: The J-MINT PRIME Kanagawa trial was an 18-month multimodal intervention (incorporating exercise, nutrition, and metabolic management) for dementia prevention. Because the primary analysis showed no significant benefits, we performed an exploratory responder analysis to identify responsive subpopulations.

METHODS: We analyzed the Full Analysis Set comprising 188 participants. Classification and regression tree (CART) analysis, applied to the intervention arm, identified baseline predictors of cognitive improvement. These rules were then applied to the entire cohort to evaluate treatment effects on the Mini-Mental State Examination (MMSE) using fully adjusted mixed-effects models for repeated measures (MMRM).

RESULTS: CART identified a "Target Group" (N = 108) characterized by baseline profiles such as an MMSE score < 28 or specific metabolic ranges (e.g., LDL-C < 135 mg/dL). Within this target group, the intervention significantly preserved MMSE trajectories compared with the control group (group × time interaction, P = 0.022). In contrast, the Non-Target Group (N = 80), consisting of high-functioning individuals (MMSE ≥ 28), exhibited no significant group × time interaction.

DISCUSSION: Multimodal interventions may effectively preserve global cognition in older adults with sub-threshold cognitive decline. Careful targeting of appropriate populations, while considering potential longitudinal measurement artifacts (e.g., practice effects), is essential. These findings provide a hypothesis-generating framework that warrants external validation in future prevention trials.},
}

@article {pmid42134046,
year = {2026},
author = {Chu, TDX and Hui, LM and Khatri, N and Jean Chen, J},
title = {Resilience to mid-to-late-life depression as a risk factor for Alzheimer's disease: Physiological factors and the role of neuroimaging.},
journal = {Neurobiology of aging},
volume = {166},
number = {},
pages = {1-13},
doi = {10.1016/j.neurobiolaging.2026.05.004},
pmid = {42134046},
issn = {1558-1497},
abstract = {Depression and Alzheimer's Disease (AD) are both diagnosed in women twice as often as in men. Moreover, a history of untreated depression confers a 2-to-5-fold increase in the risk of developing dementia. Finally, biological factors such as sex differences in immune response increase rates of depressive pathology among women. Importantly, the prevalence of mid-to-late-life depression (MLD) worldwide and its misdiagnosis due to clinical overlap with AD hinder accurate assessment and timely treatment of depression among older adults. Correct diagnosis of depression and AD using neuroimaging will enable early adoption of appropriate management, which will improve cognitive resilience. In the context of neural resilience in late-life depression, this review discusses the involvement of sex-related risk factors such as differences in immune response, and the importance of understanding the mid-life neurological signature of depression. We focus on the role of diffusion-weighted magnetic resonance imaging (MRI), which is also specifically linked to the presence of neuroinflammation in depression and the ability to distinguish it from AD despite cognitive overlaps in clinical manifestation. This review highlights the importance of sex differences in promoting resilience against MLD and AD-related declines, and supports neuroimaging as a feasible approach to advance our understanding of the role of neuroinflammation in both depression and Alzheimer's disease as a sex-dependent phenomenon.},
}

@article {pmid42134309,
year = {2026},
author = {Lee, J and Zhu, Y and Tseng, HR},
title = {Bioorthogonal Click Chemistry-Enabled Enrichment of Extracellular Vesicles for Integrated Molecular and Functional Liquid Biopsy§.},
journal = {Accounts of chemical research},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.accounts.6c00091},
pmid = {42134309},
issn = {1520-4898},
abstract = {ConspectusExtracellular vesicles (EVs) are lipid bilayer-enclosed nanoparticles released by virtually all cells, carrying protected lipids, nucleic acids, proteins, and active enzymes that faithfully reflect the physiological and pathological states of their cellular origins. Tumor- and neuron-derived EVs are abundantly present in peripheral blood, even at early disease stages, and thus represent highly attractive substrates for liquid biopsy. However, the clinical translation of EV-based diagnostics has been constrained by a central challenge: the inability to selectively enrich disease-relevant EVs from a vast background of normal EVs with sufficient specificity, efficiency, and compatibility for seamless integration with downstream molecular and functional analyses. Conventional physical isolation approaches generate heterogeneous EV mixtures that dilute disease-specific signals, whereas traditional immunoaffinity capture often suffers from nonspecific interactions and low recovery due to sparse and heterogeneous antigen density on EV membranes.To overcome these limitations, our laboratory has developed a chemical biology solution utilizing the bioorthogonal inverse-electron-demand Diels-Alder reaction between trans-cyclooctene (TCO) and tetrazine (Tz). By labeling tumor or neuronal EVs in plasma with TCO-grafted antibodies and covalently immobilizing them onto Tz-functionalized substrates, our three EV enrichment platforms, namely, EV Click Chips, EV Click Beads, and EV Click MagBeads, enable rapid, irreversible, and highly specific capture of defined EV subpopulations. These click chemistry-mediated enrichment strategies reduce nonspecific binding, markedly improve capture efficiency, and preserve EV integrity, providing a robust foundation for downstream genetic, proteomic, and functional analyses. Building on this chemical biology solution, we established three complementary EV assay modalities. Platform #1, the EV Digital Scoring Assay, couples click chemistry-mediated EV enrichment with RT-digital PCR to quantify tumor-specific mRNAs or oncogenic mutations. This "enrich-then-count" strategy has demonstrated strong clinical utility in early detection of hepatocellular carcinoma (HCC), molecular staging of prostate cancer, and detection of actionable gene alterations in pancreatic cancer and Ewing sarcoma. A refined version enables real-time HCC treatment-response monitoring, outperforming serum AFP and radiographic criteria in monitoring treatment responses. Platform #2, the EV Surface Protein Assay, uses antibody-directed click enrichment followed by immuno-PCR or RT-qPCR to quantify tumor-specific EV subpopulations. Analogous to tissue immunohistochemistry but executed in a liquid-biopsy format, this assay has shown accuracy in early detection of HCC, pancreatic ductal adenocarcinoma, and epithelial ovarian cancer and supports longitudinal monitoring in prostate and thyroid cancers. Platform #3, the EV Protease Activity Assay, extends EV analysis into functional biology by measuring enzymatic activities preserved within enriched EVs. In osteosarcoma, matrix metalloproteinase activity profiles stratified localized versus metastatic disease and tracked therapeutic response. In neurology, quantifying β-secretase activity in neuronal EVs enabled highly accurate detection of early Alzheimer's disease and correlated with cognitive performance.Together, these TCO-Tz click chemistry-enabled platforms provide a modular, robust, and clinically adaptable toolkit for noninvasive EV-based diagnostics. By uniting chemical precision with biological and clinical relevance, this framework advances the broader vision of real-time, disease-specific liquid biopsy across oncology and neurodegeneration, laying the foundation for next-generation integrated diagnostic systems.},
}

@article {pmid42134480,
year = {2026},
author = {Wu, Q and Cui, X and Liu, X and Yuan, X and Wang, P and Li, H and Xiu, R},
title = {Tetramethylpyrazine improving cerebral microcirculation in Alzheimer's Disease mice.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111936},
doi = {10.1016/j.brainresbull.2026.111936},
pmid = {42134480},
issn = {1873-2747},
abstract = {Cerebrovascular dysfunction plays a crucial role in the development and progression of Alzheimer's Disease (AD). Tetramethylpyrazine, a bioactive alkaloid monomer derived from Chinese herbal medicine Chuanxiong (Ligusticum chuanxiong), has been demonstrated to improve tissue microcirculation. However, direct in vivo monitoring of cerebral microcirculation is still challenging due to the presence and thickness of the skull. In this study, we constructed a visualized mouse cranial window and utilized photoacoustic microscopy, laser speckle imaging, and Laser Doppler flowmetry to investigate the effect of Tetramethylpyrazine on cortical microvascular function in normal mice, AD mice, and Tetramethylpyrazine-treated AD mice. Our results revealed impaired cerebral microvascular perfusion in AD mice, including significant reductions in blood flow velocity, oxygen saturation, and metabolic rate of oxygen. Tetramethylpyrazine treatment improved cortical microvascular function in AD mice, with endothelium-derived microvascular signals playing a key role in microvascular rhythmic motion. These findings suggest that Tetramethylpyrazine has the ability to enhance cortical microcirculation in AD mice through multiple mechanisms, particularly through endothelial improvement. Tetramethylpyrazine may serve as a potential candidate drug for AD treatment, and photoacoustic microscopy holds promise in the clinical observation of cortical microcirculation in AD.},
}

@article {pmid42134886,
year = {2026},
author = {Chinnathambi, S and Rangappa, N},
title = {Biosimilars: Antibody and nanobody-based therapeutic approaches towards protein misfolding diseases.},
journal = {Advances in protein chemistry and structural biology},
volume = {151},
number = {},
pages = {157-195},
doi = {10.1016/bs.apcsb.2025.10.014},
pmid = {42134886},
issn = {1876-1631},
mesh = {Humans ; *Biosimilar Pharmaceuticals/therapeutic use/chemistry/pharmacology ; *Proteostasis Deficiencies/drug therapy/metabolism/pathology ; *Single-Domain Antibodies/therapeutic use ; Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; *Alzheimer Disease/drug therapy/metabolism/pathology ; tau Proteins/metabolism/antagonists & inhibitors/immunology ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; alpha-Synuclein/metabolism/antagonists & inhibitors ; *Parkinson Disease/drug therapy/metabolism/pathology ; },
abstract = {Neurodegenerative diseases, such as Alzheimer's disease, and Parkinson's disease, are characterized by progressive neuronal dysfunction and degeneration. These conditions often share pathological hallmarks such as protein misfolding, oxidative stress, neuroinflammation, and mitochondrial dysfunction. This review focuses on key pathological players like Tau and Amyloid-beta in Alzheimer's disease, highlighting their roles in microtubule destabilization, synaptic dysfunction, and neuronal death. The interplay between oxidative stress and these proteinopathies exacerbates neurodegeneration. Recent advances in therapeutic strategies are also explored, particularly the promise of biosimilars, cost-effective alternatives to biologics, targeting pathological hallmarks in neurodegenerative diseases. Biosimilars targeting Tau and Amyloid-beta in Alzheimer's disease, and alpha-synuclein in Parkinson's disease, hold the potential to improve treatment accessibility and reduce economic burdens. However, their development is still in its early stages. This review underscores the urgent need for innovative, affordable, and globally accessible therapeutic solutions to address the rising burden of neurodegenerative diseases.},
}

Humans
*Biosimilar Pharmaceuticals/therapeutic use/chemistry/pharmacology
*Proteostasis Deficiencies/drug therapy/metabolism/pathology
*Single-Domain Antibodies/therapeutic use
Amyloid beta-Peptides/metabolism/antagonists & inhibitors
*Alzheimer Disease/drug therapy/metabolism/pathology
tau Proteins/metabolism/antagonists & inhibitors/immunology
*Neurodegenerative Diseases/drug therapy/metabolism
Animals
alpha-Synuclein/metabolism/antagonists & inhibitors
*Parkinson Disease/drug therapy/metabolism/pathology

@article {pmid42134887,
year = {2026},
author = {Chinnathambi, S},
title = {Induced-pluripotent stem cell-derived immunotherapy for Tau and Alzheimer's disease.},
journal = {Advances in protein chemistry and structural biology},
volume = {151},
number = {},
pages = {197-224},
doi = {10.1016/bs.apcsb.2025.10.005},
pmid = {42134887},
issn = {1876-1631},
mesh = {*Alzheimer Disease/therapy/immunology/pathology/metabolism ; Humans ; *Induced Pluripotent Stem Cells/cytology/metabolism/immunology ; *tau Proteins/immunology/metabolism ; *Immunotherapy ; Animals ; },
abstract = {Neurodegenerative diseases, such as Alzheimer's disease, are characterized by progressive neuronal death and functional decline. Key pathological hallmarks of Alzheimer's disease include the deposition of aggregated amyloid-β (Aβ) proteins into extracellular plaques and the accumulation of hyperphosphorylated Tau protein into intracellular aggregates. These toxic species triggers neuroinflammation through interactions with glial cells, further exacerbating neurodegeneration. This study explores the potential of induced pluripotent stem cells (iPSCs) in disease modelling, focusing on their application in modelling Alzheimer's disease pathology and therapeutic screening. Additionally, the development of advanced 3D culture systems and organoids offers insights into human-specific Alzheimer's disease mechanisms, overcoming limitations of traditional 2D and animal models. The focus is on the role of microglial polarization in neuroinflammation and its potential therapeutic modulation, offering a promising approach for the treatment of neurodegenerative diseases.},
}

*Alzheimer Disease/therapy/immunology/pathology/metabolism
Humans
*Induced Pluripotent Stem Cells/cytology/metabolism/immunology
*tau Proteins/immunology/metabolism
*Immunotherapy
Animals

@article {pmid42135923,
year = {2026},
author = {Mia, E and Hossain, MA and Bristy, AH and Hossan, R and Asif, U and Sherwani, AK and Alshahrani, MY and Selim, S and Rakib, IH and Yana, NT and Akter, K and Hasan, MSA},
title = {Neuroprotective Properties of Litchi chinensis and Its Phytochemicals in Preclinical Models of Alzheimer's Disease.},
journal = {Brain and behavior},
volume = {16},
number = {5},
pages = {e71474},
doi = {10.1002/brb3.71474},
pmid = {42135923},
issn = {2162-3279},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Litchi/chemistry ; Animals ; *Neuroprotective Agents/pharmacology ; Disease Models, Animal ; *Phytochemicals/pharmacology ; *Plant Extracts/pharmacology ; Humans ; Rats ; Oxidative Stress/drug effects ; Mice ; Amyloid beta-Peptides/metabolism ; },
abstract = {PURPOSE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder involving amyloid-β deposition, tau hyperphosphorylation, oxidative stress, and neuroinflammation. This review systematically evaluates the neuroprotective effects of Litchi chinensis and its phytochemicals against AD, focusing on modulation of Aβ accumulation, tau pathology, oxidative stress, neuroinflammation, apoptosis, and synaptic dysfunction using available preclinical evidence.

METHOD: A systematic literature search was conducted in PubMed, Scopus, Web of Science, ScienceDirect, and Google Scholar up to August 2025 using relevant keywords. Studies investigating neuroprotective effects of Litchi chinensis extracts or compounds in in vitro or in vivo AD models were included, while unrelated studies, duplicates, abstracts, and non-full-text articles were excluded.

RESULTS: Litchi chinensis extracts and phytochemicals demonstrated broad neuroprotective actions. In triple-transgenic mice, oligonol treatment (0.25-0.50 mg/mL) significantly reduced amyloid precursor protein (APP), β-secretase, and amyloid-β levels, while also decreasing tau hyperphosphorylation. Seed extracts (0.7-2.8 g/kg/day) reduced amyloid-β accumulation and neuronal injury in Sprague-Dawley rats. Anti-inflammatory effects were evident through decreased tumor necrosis factor-α, IL-1β, IL-6, and interferon gamma, alongside increased IL-4. Antioxidant defenses were enhanced via upregulation of antioxidant enzymes such as glutathione peroxidase-1 and superoxide dismutase-2, while apoptosis was suppressed by increasing Bcl-2 and reducing Bax and caspase activity. Synaptic integrity was preserved through upregulation of PSD95, synaptophysin, and serotonin receptor proteins, resulting in improved learning and memory in AD models. Additional benefits included enhanced mitochondrial and proteasomal activity, alleviation of endoplasmic reticulum (ER) stress, and induction of neurotrophic factors like insulin-like growth factor 2 and fibroblast growth factor 21.

CONCLUSION: Litchi chinensis demonstrates a multitargeted neuroprotective role, making it a promising natural therapeutic candidate for Alzheimer's management. However, as most findings are limited to preclinical models, further clinical studies are necessary to validate efficacy, ensure safety, and explore its translational potential.},
}

*Alzheimer Disease/drug therapy/metabolism
*Litchi/chemistry
Animals
*Neuroprotective Agents/pharmacology
Disease Models, Animal
*Phytochemicals/pharmacology
*Plant Extracts/pharmacology
Humans
Rats
Oxidative Stress/drug effects
Mice
Amyloid beta-Peptides/metabolism

@article {pmid42136137,
year = {2026},
author = {Bao, L and Zhao, F and Xu, W and Jiang, P and Zhang, Y and Luo, Y and Guan, W and Li, M and Chen, Q and Zhang, L and Kuang, H and Li, J and Liu, Y},
title = {Pharmacodynamics and mechanisms of triterpene components from the leaves of Astragalus mongholicus Bunge in the treatment of Alzheimer's disease.},
journal = {Natural product research},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/14786419.2026.2671969},
pmid = {42136137},
issn = {1478-6427},
abstract = {This study investigates the therapeutic potential and underlying mechanisms of triterpenoids (TR) derived from the leaves of Astragalus mongholicus Bunge for the treatment of Alzheimer's disease (AD). Eighteen triterpenoid compounds were identified in the TR fraction using UPLC-Q-TOF-MS. In the 3 × Tg-AD transgenic mouse model, the therapeutic efficacy of TR was assessed using a comprehensive approach that included the Morris water maze, histopathological analysis, transmission electron microscopy, and Western blotting. The findings revealed that TR significantly improved spatial learning and memory impairments, reduced hippocampal neuronal degeneration, and diminished the deposition of phosphorylated Tau (p-Tau) protein. Ultrastructural examination further confirmed that TR preserved mitochondrial integrity. Mechanistic studies showed that TR upregulated key mitophagy-related proteins in both PINK1/Parkin-dependent and -independent pathways. In conclusion, TR exerts neuroprotective effects by activating mitophagy through multiple pathways, highlighting its potential as a promising therapeutic candidate for AD. This study not only provides experimental evidence for the therapeutic potential of natural products targeting mitophagy in Alzheimer's disease but also expands the medicinal development value of the leaves of Astragalus mongholicus Bunge.},
}

@article {pmid42136262,
year = {2026},
author = {Khan, MA and Khan, ZA and Shoeb, F and Siddiqui, Z and Pandey, G and Fatima, G and Khan, RH and Khan, MM},
title = {Role of De Novo Lipogenesis in Neurodegeneration and Neurogenesis Disruption in Alzheimer's Disease and Treatment Perspective.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X423516260216052123},
pmid = {42136262},
issn = {1875-6190},
abstract = {Progressive neurodegeneration, decline in neurogenesis, and cognitive dysfunction alongside amyloid-β plaque and neurofibrillary tangle formation are prominent pathological features of Alzheimer's Disease (AD). Although the underlying mechanism remains unclear, evidence suggests that surplus intracellular lipids/fatty acids could be the primary mediators. In this regard, increased levels of Saturated Fatty Acids (SFAs), Monounsaturated Fatty Acids (MUFAs), their triglyceride and ceramide derivatives have been reported in the brain of patients with AD. Further, converging evidence from basic and clinical studies suggests that de novo lipogenesis could be the main source of lipid/fatty acid accumulation in the brains of patients with AD. Although elevated cholesterol has long been suggested to induce inflammation and neurodegenera-tion in AD, recent evidence suggests that the effects of SFAs and their lipid derivatives, particularly ceramides, could be more detrimental. Consequently, de novo lipogenesis inhibitors could be the potential therapeutic targets for the early intervention in AD. Intriguingly, several studies have shown that treatment with various natural or synthetic compounds, which inhibit de novo lipogenesis, effectively reduced neurodegeneration, cognitive dysfunction, and inflammation in the model animals of AD. These compounds also increased neurogenesis while reducing lipid/fatty acid accumulation, suggesting that blocking lipid/fatty acid biosynthesis by inhibiting de novo lipogenesis could be an effective strategy in treating AD. Thus, while the study discusses the effects of various FDA-approved AD drugs and selected natural and synthetic inhibitors of de novo lipogenesis on neurodegeneration and neurogenesis in model animals, the doors are open for conducting clinical trials in patients with AD.},
}

@article {pmid42136266,
year = {2026},
author = {Gupta, S and Nihal, PM and Jawaid, T and Ashesh, AM and Bhise, MR and Rawat, M and Lohidasan, S and Wal, P and Kumar, A and Kumar, D and Gasmi, A},
title = {Exploring Mitochondrial Dysfunction and Protective Therapeutic Approaches to Counteract Its Role in Alzheimer's Disease Progression.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X419571260226033536},
pmid = {42136266},
issn = {1875-6190},
abstract = {Alzheimer's disease (AD) is the primary cause of dementia, characterized by a progres-sive decrease in mental abilities and the accumulation of amyloid-beta (Aβ) peptides in the brain. The combination of these peptides leads to the development of neuritic plaques and neurofibrillary tangles that disrupt neural communication and eventually lead to the loss of neurons. One of the fac-tors that are involved in the development of AD is mitochondrial dysfunction. Disrupted function-ing of mitochondria leads to the production of less energy by the cells, increased oxidative stress, and accelerates the neurodegeneration process. Neurons that carry out their mitochondrial functions normally are required to keep the balance of calcium, in a reasonable energy production, and in the survival of the cells. Mitophagy, which guarantees the clearing of damaged mitochondria, is im-paired in AD. Cholinesterase blockers and NMDA receptor blockers are currently used as treat-ments, but these are not aimed at the underlying pathophysiology of the condition. New treatment approaches that are aimed at enhancing mitochondrial health, in contrast, are viable at providing a potential to decelerate or alter mitochondrial AD progression. The goals of these approaches include enhancement of the mitophagy process, alleviation of oxidative stress, and preservation of mito-chondrial health, which may disrupt major pathological events such as Aβ aggregation and tau hy-perphosphorylation. By concentrating on the replacement of mitochondria, scientists are moving in the right direction to develop therapies that will not only help control the symptoms but also cure the disease.},
}

@article {pmid42136278,
year = {2026},
author = {Sharma, A and Mittal, V and Sharma, D and Deswal, G and Das, A and Guarve, K and Grewal, AS},
title = {Therapeutic Insights into Natural Products for Modulating Neurodegenerative Disease Pathways.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249405308251210104405},
pmid = {42136278},
issn = {1875-6166},
abstract = {INTRODUCTION: Neurodegenerative Disorders (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis (ALS), are chronic and progressive conditions marked by the gradual loss of neuronal structure and function. These disorders lead to cognitive, motor, and sensory decline, significantly reducing quality of life and posing a major global health burden due to rising healthcare costs and the absence of curative therapies. This review aims to comprehensively explore the therapeutic potential of natural products in targeting cellular and molecular mechanisms underlying NDs, highlighting their neuroprotective roles and potential for disease modification.

METHODS: A comprehensive literature review was conducted using databases including PubMed, Scopus, Web of Science, and Google Scholar. Peer-reviewed articles, clinical trials, and experimental studies were analyzed to evaluate the therapeutic potential of natural products and their bioactive compounds in the management of NDs.

RESULTS: ND pathogenesis involves oxidative stress, neuroinflammation, mitochondrial dysfunction, and abnormal protein aggregation, ultimately leading to neuronal death. Current therapies largely provide symptomatic relief without altering disease progression. Natural products from plants, fungi, and marine sources demonstrate strong neuroprotective potential through multitargeted mechanisms. Bioactive compounds such as flavonoids, alkaloids, terpenoids, and polyphenols exhibit antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective activities. Key molecules, including curcumin, resveratrol, luteolin, quercetin, and catechins, modulate signaling pathways such as NF-κB, MAPK, PI3K/AKT, Nrf2, apoptosis, and autophagy, thereby reducing amyloid-beta aggregation, protecting dopaminergic neurons, improving mitochondrial function, and enhancing cognition in preclinical and clinical studies.

DISCUSSION: Natural products represent promising candidates for disease modification in NDs due to their multi-pathway actions and relatively low toxicity. However, major limitations, such as poor bioavailability, pharmacokinetic variability, and the lack of standardized formulations, hinder clinical translation. Innovative strategies, including advanced drug-delivery systems, structural modifications, and synergistic formulations, are needed to overcome these barriers.

CONCLUSION: Natural products hold significant therapeutic potential in managing neurodegenerative diseases by targeting multiple pathological mechanisms. Their integration into ND treatment could provide safer and more effective alternatives, but further well-designed clinical trials are essential to establish their efficacy and facilitate clinical application.},
}

@article {pmid42136282,
year = {2026},
author = {Singh, P and Bhardwaj, S and Nagarajan, K},
title = {Development and Assessment of Phytoconstituents-based Nanoemulsion as a Potent Combined Therapy for Neuroprotection in Scopolamine-induced Alzheimer's Disease Rat Model.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026450795260413103307},
pmid = {42136282},
issn = {1875-5739},
abstract = {INTRODUCTION: Nanoemulsions are increasingly recognized as effective carriers for delivering neuroprotective agents in the management of neurodegenerative conditions like Alzheimer's disease. Alzheimer's Disease (AD) is a chronic and progressive neurological disorder marked by memory impairment, cognitive dysfunction, oxidative damage, and degeneration of neurons. This study focuses on designing and evaluating a nanoemulsion-based drug delivery system combining Resveratrol and Ginkgo biloba to investigate their potential neuroprotective effects in a scopolamine- induced Alzheimer's model in Wistar rats.

METHODS: A total of nine water-in-oil nanoemulsion formulations (F1-F9) were developed using probe sonication and examined for various parameters, including droplet size, zeta potential, polydispersity index (PDI), entrapment efficiency, and in vitro drug release profiles.

RESULTS: Among these, Formulation F2, containing 25 mg of Resveratrol and 25 mg of Ginkgo biloba, showed the most favourable characteristics, including a high entrapment efficiency of 90.13%, maximum drug release of 92.33%, a particle size of 92.83 nm, and a zeta potential of 30.75 mV, suggesting good stability of the formulation. For the in vivo evaluation, rats were divided into six groups: normal control, negative control (scopolamine-treated), standard treatment group (Diazepam 2 mg/kg), and three test groups with different formulations. Behavioural studies using the Y-maze demonstrated that the Test Group 1 (treated with F2 formulation) had significantly improved spontaneous alternation behaviour, indicating enhanced cognitive performance. Biochemical analysis showed reduced malondialdehyde (MDA) levels and increased glutathione (GSH) levels, suggesting potent antioxidant activity. Additionally, histopathological examination of brain tissue revealed that the F2-treated group showed reduced neuronal damage and better preservation of hippocampal structure.

DISCUSSION: In rats treated with scopolamine, the optimized F2 nanoemulsion showed excellent physicochemical stability and markedly enhanced cognitive function. Strong antioxidant and neuroprotective effects of the combination formulation are indicated by decreased MDA levels, increased GSH levels, and intact hippocampus architecture.

CONCLUSION: The Resveratrol-Ginkgo biloba nanoemulsion (F2) successfully reduced oxidative stress and cognitive impairment, indicating its potential as a treatment for early-stage Alzheimer's disease. Additional research is needed to confirm its therapeutic application.},
}

@article {pmid42136286,
year = {2026},
author = {Tiwari, P and Kadiri, SK and Sulakhiya, K},
title = {Hyperprolactinemia and Tau Pathology: Unravelling Neuroendocrine Dysregulation for Therapeutic Targeting.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026467094260417052012},
pmid = {42136286},
issn = {1875-5739},
abstract = {BACKGROUND: Hyperprolactinemia, characterized by persistently elevated serum prolactin levels, is traditionally associated with reproductive and metabolic disturbances. Emerging evidence now implicates hyperprolactinemia in central nervous system dysfunction, particularly in the pathogenesis of neurodegenerative disorders. Chronic elevation of prolactin has been linked to tau pathology, a hallmark of Alzheimer's disease and related tauopathies, through mechanisms that promote tau hyperphosphorylation, microtubule destabilization, and neuronal compromise.

METHODOLOGY: This systematic review assesses the evidence on hyperprolactinemia and tau pathology. The overall literature search was performed in PubMed, Scopus, and Web of Science with the help of certain keywords that included prolactin, tau protein, neuroinflammation, oxidative stress, and dopaminergic signaling. The studies were narrowed down to a set of pre-established inclusion and exclusion criteria (original research, molecular and clinical data, relevance to neuropsychiatric disorders, non-English articles, reviews, animal studies that did not have a translational relevance). A clear study selection procedure was used, with independent screening and consensus-based resolution. The results generalize molecular, transcriptomic, neuroimaging, and clinical data to assess mechanistic connections and treatment prospects.

RESULTS: Neurons susceptible to tau accumulation under hyperprolactinemic states exhibit altered apoptotic signaling, impaired vesicular trafficking, and mitochondrial dysfunction. These disruptions correlate with increased neuroinflammation and oxidative stress, suggesting a mechanistic link between endocrine imbalance and tau-mediated neurotoxicity. Therapeutic agents such as dopamine agonists, selective kinase inhibitors, and prolactin receptor antagonists have the potential to restore neuroendocrine homeostasis and mitigate tau pathology.

DISCUSSION: The findings underscore hyperprolactinemia as a modifiable risk factor for cognitive decline. The neuroendocrine-tau axis represents a critical interface where hormonal dysregulation may precipitate neurodegenerative cascades. Clinical implications in the manuscript include that prolactin may serve as a biomarker of an early neurodegenerative process and that its role in the treatment approach includes dopamine agonists, prolactin receptor antagonists, and kinase inhibitors. This simplified methodology will ensure the highlights are original and have translational implications beyond mere abstract repetition.

CONCLUSION: Hyperprolactinemia-induced tau dysregulation presents novel opportunities for neuroprotective targeting. By bridging molecular mechanisms with clinical relevance, this review advocates for longitudinal studies to assess cognitive outcomes in hyperprolactinemic individuals. Emphasizing endocrine health may enhance cognitive resilience and inform future strategies for diagnosis, risk stratification, and therapeutic intervention in neurodegenerative diseases.},
}

@article {pmid42136293,
year = {2026},
author = {Ramesh, J and Jayanthi, B and Mohan, VK and Srinivasan, S and Vijayalakshmi, MK and Mohan, M},
title = {Targeted Nanotechnology Approaches to Bypass the Blood-brain Barrier in Neurodegenerative Disorders.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273444679260416064255},
pmid = {42136293},
issn = {1996-3181},
abstract = {Neurodegenerative diseases like Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's disease (HD) are a growing health burden across the world because of the progressive loss of brain cells and the ineffective nature of the available treatment. One significant challenge in the treatment of these conditions is the Blood- -Brain Barrier (BBB), a highly selective interface that limits the access of most therapeutic molecules to the central nervous system. Nanotechnology has become an attractive approach to addressing this difficulty, as it enables the delivery of drugs with high accuracy and actively engages in the repair of the BBB. This review provides an overall synthesis of focused nanotechnology solutions aimed at both circumventing and restoring BBB function in neurodegenerative illnesses. It discusses various nanoparticle (NP) platforms such as polymeric, lipid-based, micellar, metallic, and carbon-derived systems in the light of their physicochemical aspects, transport across the BBB, and therapeutic efficacy. Particular emphasis is put on the receptor-mediated transcytosis, neurovascular unit modulations, and the regulation of Wnt, Shh, and Tie-2 signalling pathways, which are BBB integrity pathways. The review incorporates mechanisms of BBB repair in combination with neuroprotective nanotherapies, rather than focusing solely on end repair. This review covers the role of targeted nanotechnology in the future of therapeutic approaches for neurodegenerative diseases. By connecting materials science, molecular neuroscience, and clinical innovation, it demonstrates how next-generation brain-targeted therapies can be developed using targeted nanotechnology.},
}

@article {pmid42136299,
year = {2026},
author = {Xia, B and Wu, S and Yu, W and Lü, Y},
title = {Research Progress on Intervention Strategies Targeting the Gut-Brain Axis in Alzheimer`s Disease.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273431295251201140053},
pmid = {42136299},
issn = {1996-3181},
abstract = {As the most common neurodegenerative disease in the world, Alzheimer's Disease (AD) is characterized by a complex pathogenesis and a lack of effective treatments. In recent years, breakthroughs in the Gut-Brain Axis (GBA) theory have provided a new direction for AD intervention. Studies have shown that AD patients commonly exhibit gut dysbiosis, accompanied by decreased Short-Chain Fatty Acid (SCFA) levels, endotoxin leakage, and increased systemic inflammation, which accelerate cognitive decline via neuroinflammation, Aβ deposition, and synaptic dysfunction. Based on this, intervention strategies targeting the GBA have emerged as a focus of research for slowing down the pathological process of AD. In this study, we systematically summarize the mechanisms linking gut microbiota dysbiosis to AD pathology. This includes the roles of metabolites (e.g., SCFA, LPS, and TMAO) in modulating neuroinflammation and Blood-Brain Barrier (BBB) permeability, as well as the critical involvement of vagal nerve pathways in gut-brain signaling. We further explored the potential of probiotics to improve cognitive function by restoring microbial homeostasis, enhancing anti-inflammatory effects, and elevating neurotrophic factor levels; dietary interventions (e.g., the Mediterranean and MIND diets) to reduce AD risk by modulating microbial composition and metabolic activity; and Fecal Microbiota Transplantation (FMT) to reduce Aβ plaque deposition and mitigate neuroinflammation. Despite promising findings, challenges persist, including discrepancies between animal models and human subjects, individual variability in microbiota composition, and an incomplete understanding of underlying mechanisms. In the future, it will be necessary to combine multiple technologies to develop personalized intervention protocols and optimize clinical translation processes, providing a theoretical basis for the precise treatment of AD.},
}

@article {pmid42136342,
year = {2026},
author = {Liu, CW and Shan, ZX and Li, WJ and Qu, QW and Hou, XQ},
title = {Potential Therapeutic Effects and Mechanisms of Estrogen on Diabetes, Alzheimer's Disease,and Their Comorbidity:A Review.},
journal = {Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae},
volume = {48},
number = {2},
pages = {328-337},
doi = {10.3881/j.issn.1000-503X.16649},
pmid = {42136342},
issn = {1000-503X},
mesh = {Humans ; *Alzheimer Disease/drug therapy/epidemiology ; *Estrogens/therapeutic use ; *Diabetes Mellitus/drug therapy/epidemiology ; Comorbidity ; },
abstract = {Estrogen is a lipid-soluble steroid hormone and one of the most important female sex hormones.It mainly functions by interacting with estrogen receptors,maintaining normal physiological and pathophysiological functions of the body,and playing a crucial role in regulating blood glucose homeostasis,metabolism,and physiological processes associated with brain learning and memory.Recent studies have shown that estrogen has potential therapeutic effects on diabetes,cognitive impairment and other diseases.It will provide new ideas and treatment strategies for diabetes,Alzheimer's disease,and their comorbidity by regulating the activity of estrogen and the interaction with estrogen receptors to modulate related pathological and physiological processes.This article reviews the latest research progress in the relationship between estrogen and these diseases,providing a new perspective and prospect for the prevention and treatment of diabetes,Alzheimer's disease,and their comorbidity.},
}

Humans
*Alzheimer Disease/drug therapy/epidemiology
*Estrogens/therapeutic use
*Diabetes Mellitus/drug therapy/epidemiology
Comorbidity

@article {pmid42136344,
year = {2026},
author = {Zhang, XT and Chen, SS and Liu, YW and Huang, HR and Yu, Y},
title = {Role of Brain Insulin Resistance in the Pathogenesis of Alzheimer's Disease.},
journal = {Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae},
volume = {48},
number = {2},
pages = {347-354},
doi = {10.3881/j.issn.1000-503X.16614},
pmid = {42136344},
issn = {1000-503X},
mesh = {*Alzheimer Disease/metabolism/etiology/physiopathology/pathology ; *Insulin Resistance ; Humans ; *Brain/metabolism ; },
abstract = {Alzheimer's disease (AD) is the most common type of dementia,in which brain insulin resistance (BIR) plays a key role.BIR affects the response of brain cells to insulin and is associated with cognitive decline and pathological features of AD.This study explores the role of BIR in the pathogenesis of AD and evaluates potential treatment strategies,aiming to provide new directions for the prevention and treatment of AD.},
}

*Alzheimer Disease/metabolism/etiology/physiopathology/pathology
*Insulin Resistance
Humans
*Brain/metabolism

@article {pmid42136471,
year = {2026},
author = {Sharma, S and Thakur, A and Paliwal, D and Mondal, R and Saini, S and Sahu, R and Kaushik, N and Tiwari, H},
title = {Exploring the Therapeutic Potential of Coumarin Scaffolds in Alzheimer's Disease: A Comprehensive Review.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575443995260406045449},
pmid = {42136471},
issn = {1875-5607},
abstract = {Alzheimer's disease is a progressive and debilitating form of neurological disorder that affects millions of people across the globe. Alzheimer's disease is essentially defined by the presence of cognitive decline, memory impairments, and behavioral symptoms, and it is also defined by pathological hallmarks such as amyloid plaques, Tau protein inclusions, oxidative stress, & neuroinflammation. However, despite the vast progress made in the field of neuroscience and pharmacology, there is no permanent treatment available for Alzheimer's disease, and the existing treatments are only symptomatic in nature. This has led to the search for new innovative therapeutic approaches based on small molecules with multifunctional pharmacological properties. Among different molecules, Coumarin derivatives have been identified as promising therapeutic agents owing to their high structural diversity and potent ability to bind key molecular targets involved in AD pathogenesis. Coumarin derivatives have been found to have strong potential for modulating oxidative stress, inhibitng cholinesterase, reducing neuroinflammation, and interfering with amyloid-beta aggregation. Recent advancements in the synthesis and design of coumarin derivatives have shown that slight modifications in their structure can yieldsubstantial improvements in their efficacy and selectivity in the treatment of Alzheimer's disease. For coumarin derivatives to be used in the treatment of Alzheimer's disease, they need first to be able to cross the blood-brain barrier. To overcome this limitation, scientists have been working to improve lipophilicity, optimize molecular size and polarity, and design prodrugs. This review provides an updated account of the use of coumarin derivatives in the treatment of Alzheimer's disease. It focuses on their neuroprotective and, symptommodifying effects, and their use in dealing with the multifactorial nature of the disease. Moreover, this paper aims to give recent research findings and discuss the structure-activity relationships of these compounds. The knowledge gained from this review is expected to motivate further research endeavors in the development of stronger and more specific AD drugs.},
}

@article {pmid42136472,
year = {2026},
author = {Shrivastava, N and Husain, A and Haider, K},
title = {Substituted Benzofurans as Potent Anticancer Agents: Advances, Molecular Docking, and SAR Studies.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575435772260422071930},
pmid = {42136472},
issn = {1875-5607},
abstract = {Benzofuran, an oxygen-containing fused heterocyclic aromatic compound, occurs naturally as a secondary metabolite from various plant sources like Rutaceae, Asteraceae, Cyperaceae, and Liliaceae. The derivatives of benzofuran possess a wide range of biological activities, including anticancer, anti-inflammatory, antioxidant, antibiotic, analgesic, anti-Alzheimer's, and immunosuppressive effects. Various synthetic methods are currently used to prepare various benzofuran derivatives. Its therapeutic significance is highlighted by the presence of the benzofuran core in several FDA-approved drugs. Due to the development of resistance in existing anticancer therapies, there is an urgent need for novel, effective, and safe therapeutic approaches. Many heterocyclic moieties and their structural hybrids have been explored for their potential biological activity and have attracted considerable attention as anticancer agents. Substituted benzofuran derivatives are emerging as lead candidates to meet the global challenges of cancer and its available treatment. Benzofuran has the chemical formula C8H6O. Structurally, it consists of a fused ring system: a benzene ring fused to a five-membered furan ring (with one oxygen). Both benzene and furan contribute to its aromatic character. Benzofuran heterocycle plays an important role in drug design and drug discovery due to its versatile nature. The current review summarizes the recent progress in the design, development, drug discovery, and pharmacological actions of benzofuran derivatives as anticancer agents; their molecular docking studies; and structure-activity relationships reported over the past five to six years, emphasizing fused heterocyclic analogues and their prospects to develop as lead molecules. A thorough understanding of the structure-activity relationship will provide a valuable framework for novel drug discovery and design.},
}

@article {pmid42137472,
year = {2026},
author = {Al-Karmalawy, AA and Attia, MI and Alnajjar, R and El-Shiekh, RA and Al Khatib, AO and Yousef, TA and Abdel-Sattar, E},
title = {Discovery of Caralluma-derived pregnane glycosides as potent and selective cholinesterase inhibitors: integrated in silico and in vitro evaluation.},
journal = {RSC advances},
volume = {16},
number = {27},
pages = {24903-24915},
pmid = {42137472},
issn = {2046-2069},
abstract = {Alzheimer's disease (AD) is the fourth leading cause of death among elderly people worldwide. It has a complex pathogenesis, making multitarget-directed ligands (MTDLs) a key therapeutic strategy. This study evaluated pregnane glycosides isolated from Caralluma species (Apocynaceae) as potential cholinesterase inhibitors targeting acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes for AD treatment. In silico molecular docking against AChE (PDB: 4EY7) and BuChE (PDB: 8CGO) identified caratuberside E and awdelioside B as top AChE binders (-11.09 and -11.49 kcal mol[-1], outperforming the cocrystal inhibitor at -9.52 kcal mol[-1]). For BuChE, caratuberside G and penicilloside C showed superior scores (-10.94 and -11.55 kcal mol[-1] vs. -8.89 kcal mol[-1] for the cocrystal). These results were validated by 200 ns molecular dynamics simulations (stable RMSD values) and MM-GBSA binding free-energy calculations, confirming strong interactions and favourable energetics. In vitro assays (using donepezil as reference) demonstrated potent inhibition: caratuberside E was most active against AChE (IC50 = 0.69 ± 0.07 µM), followed by awdelioside B (IC50 = 18.99 ± 0.06 µM); caratuberside G (IC50 = 1.59 ± 0.16 µM) and penicilloside C (IC50 = 12.38 ± 0.51 µM) excelled against BuChE. Collectively, these pregnane glycosides from Caralluma show promise as selective cholinesterase inhibitors and potential MTDLs for AD therapy.},
}

@article {pmid41928210,
year = {2026},
author = {Leelahavarong, P and Prawjaeng, J and Angkab, P and Wongkom, N and Scheltens, P and Srinonprasert, V and Senanarong, V},
title = {Cost-utility analysis of cerebrospinal fluid versus blood biomarkers for early detection of Alzheimer's disease and mild cognitive impairment in Thailand: a modeling study.},
journal = {BMC health services research},
volume = {26},
number = {1},
pages = {},
pmid = {41928210},
issn = {1472-6963},
abstract = {OBJECTIVE: To evaluate the cost-utility of cerebrospinal fluid (CSF) and blood-based amyloid beta biomarkers for early detection of Alzheimer’s disease and mild cognitive impairment among older Thai adults at high risk of dementia.

METHODS: We constructed a decision tree with Markov models from a societal perspective, using a 1-year cycle over a lifetime horizon and applying a 3% annual discount. Amyloid beta (Aβ)1–42 was used for CSF, while Aβ40 and Aβ42 were used for blood. Sensitivity and specificity data were primarily derived from Thai patients at Siriraj Hospital, and nonpharmacological treatment efficacy was obtained from the FINGER study. Epidemiological data, transition probabilities, and costs were collected from the literature and Siriraj Hospital; direct nonmedical costs and utility values were also obtained from Siriraj. We calculated lifetime costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs), evaluating cost-effectiveness against THB160,000 (USD4,370) per QALY. Parameter uncertainty was explored via sensitivity analyses. This is non-clinical trail study.

RESULTS: Compared with no testing, the CSF strategy yielded 0.011 additional life-years and 0.019 additional QALYs for an extra cost of THB2,589 (USD71), resulting in an ICER of THB132,961 (USD3,632) per QALY. Blood-based testing provided 0.009 additional life-years and 0.017 QALYs for an extra cost of THB15,467 (USD422), leading to an ICER of THB907,057 (USD24,776) per QALY.

CONCLUSIONS: CSF biomarker testing is cost-effective in Thailand, whereas blood-based biomarkers are not. Reducing the cost of Simoa (the technology used to measure blood biomarkers) by approximately 83% would improve the cost-effectiveness of blood-based biomarkers. Future research should enhance blood biomarker accuracy.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12913-026-14405-5.},
}

@article {pmid42125963,
year = {2026},
author = {Juday, TR and Holub, A and Mattke, S and Betts, KA and Kitchen, SA and Liu, H and Frech, FH and Khachaturian, AS},
title = {Community-Based Physician Attitudes Related to the Diagnosis and Treatment of Early Alzheimer's Disease in the United States.},
journal = {American journal of Alzheimer's disease and other dementias},
volume = {41},
number = {},
pages = {15333175261433309},
doi = {10.1177/15333175261433309},
pmid = {42125963},
issn = {1938-2731},
mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy ; United States ; Male ; Female ; *Attitude of Health Personnel ; *Neurologists/psychology ; *Cognitive Dysfunction/diagnosis/therapy ; *Physicians, Primary Care/psychology ; Middle Aged ; Early Diagnosis ; },
abstract = {The increasing incidence of Alzheimer's disease (AD) coupled with emerging diagnostics and treatments underscores the need for early detection of AD, yet identifying these individuals remains challenging. This US study sought to examine community-based physician attitudes regarding diagnosis and treatment of early AD (mild cognitive impairment [MCI] due to AD and mild AD). A total of 177 primary care physicians (PCPs) and 147 neurologists recruited through a national physician panel were surveyed about early AD diagnostic and treatment processes, and self-confidence in identifying and managing the condition. Physicians identified patient and family/caregiver involvement as critical in triggering the diagnostic process. Patterns of use of neurocognitive assessments, structural imaging tests, and AD-specific biomarkers varied between PCPs and neurologists. Confidence diagnosing and managing early AD was a concern across specialties, although was greater among PCPs. Programs promoting awareness of early AD symptoms, and emerging technologies and treatments are critical to timely management.},
}

Humans
*Alzheimer Disease/diagnosis/therapy
United States
Male
Female
*Attitude of Health Personnel
*Neurologists/psychology
*Cognitive Dysfunction/diagnosis/therapy
*Physicians, Primary Care/psychology
Middle Aged
Early Diagnosis

@article {pmid42126808,
year = {2026},
author = {Taylor, TL and Tuke, J and Fernandez, EJ and Hazel, SJ},
title = {Group training classes for dogs with canine cognitive dysfunction: effects on sleep, activity, and caregiver burden.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42126808},
issn = {2509-2723},
abstract = {Canine Cognitive Dysfunction (CCD) is a progressive neurodegenerative condition of ageing dogs, sharing pathological and clinical features with Alzheimer's disease. Despite the growing prevalence of CCD, non-pharmacological interventions for affected companion animals remain underexplored. This study evaluated the effects of structured group training classes on signs of CCD, sleep, daily activity, and caregiver burden. Forty-two dogs (≥ 8 years) with mild to moderate CCD were enrolled in either a scent-based (S; n = 21) or physical structured training (PST; n = 21) program. Each dog completed five consecutive weekly sessions, with outcomes assessed through the Canine Dementia Scale (CADES), accelerometry (FitBark), and validated caregiver burden measures at baseline, treatment, and post-treatment. CCD scores remained stable across all phases, suggesting no measurable cognitive changes. However, a significant interaction between training type and treatment phase was observed for sleep: dogs in the PST group demonstrated improved Fitbark sleep scores over time, while those in the S group declined. Daily activity followed expected bimodal patterns, with scent-trained dogs exhibiting reductions in morning and evening activity peaks. Caregiver burden decreased significantly across time in both groups, and caregivers reported high satisfaction with class participation, citing enhanced confidence and social support. These findings indicate that while structured training did not alter CCD severity scores, PST was associated with a small improvement in sleep, S was associated with reduced activity, and participation in both classes was linked to reduced caregiver burden. Further research is needed to confirm these changes and determine their effect on dog and human wellbeing. Group training classes may represent an accessible, welfare-focused intervention for managing CCD in companion dogs.},
}

@article {pmid42127455,
year = {2026},
author = {Tzieras, I and Manolopoulos, A and Tweedie, D and Luo, W and Maccecchini, M and Egan, JM and Greig, NH and Kapogiannis, D},
title = {A phase 1, safety, tolerability, and pharmacokinetics study of bisnorcymserine, a highly selective inhibitor of butyrylcholinesterase.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {3},
pages = {e00918},
doi = {10.1016/j.neurot.2026.e00918},
pmid = {42127455},
issn = {1878-7479},
abstract = {Cholinergic deficiency is a hallmark neurotransmitter abnormality in Alzheimer's disease (AD) that has traditionally been addressed with cholinesterase inhibitors. In severe AD, butyrylcholinesterase (BuChE) becomes the dominant cholinesterase, suggesting a potential therapeutic target. (-)-N1,N8-bisnorcymserine tartrate (BNC) is a selective BuChE inhibitor designed to address this unmet need. We conducted a phase I, single-center, randomized, double-blind, placebo-controlled, ascending single oral dose clinical trial to evaluate the safety, tolerability, and pharmacokinetics of BNC in 30 healthy volunteers. There were no adverse events (AEs) grade 2 or above or any serious adverse events (SAEs). Most events were mild and self-limited, the most common being asymptomatic bradycardia and headache. The mean AUClast (SD) was 120.98 h∗ng/mL (74.30) for the 40 mg dose, 148.20 h∗ng/mL (99.43) for the 80 mg dose, and 196.33 h∗ng/mL (91.74) for the 120 mg dose. Accordingly, median tmax (range) and mean Cmax (SD) were 1.8 (1.0-5.0) hr and 13.94 (7.64) ng/mL for the 40 mg dose, 1.8 (1.5-5.0) hr and 18.54 (6.44) ng/mL for the 80 mg dose, and 2 (1.0-4.5) hr and 20.93 (5.00) ng/mL for the 120 mg dose. The mean half-life of BNC ranged from 5.5 to 7 h. BNC was safe and well tolerated when administered as a single oral dose of up to 120 mg. This first-in-human, phase I study permits further investigation of this drug as a potential symptomatic treatment for AD. ClinicalTrials.gov, NCT01747213.},
}

@article {pmid42128444,
year = {2026},
author = {Atri, A and Apostolova, LG and Iwata, A and Wessels, AM and Atkins, A and Lu, M and Ye, W and Ryan, S and Doty, EG},
title = {Clinical Meaningfulness of Donanemab in Early Symptomatic Alzheimer Disease: Data From the Randomized Phase 3 TRAILBLAZER-ALZ 2 Trial.},
journal = {Neurology. Clinical practice},
volume = {16},
number = {3},
pages = {e200621},
doi = {10.1212/CPJ.0000000000200621},
pmid = {42128444},
issn = {2163-0933},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Aged ; *Cognitive Dysfunction/drug therapy ; Male ; Female ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology ; Aged, 80 and over ; Disease Progression ; Activities of Daily Living ; *Outcome Assessment, Health Care ; },
abstract = {BACKGROUND AND OBJECTIVES: Understanding the meaningfulness of clinical trial outcomes is essential for people living with Alzheimer disease (AD) and their clinicians to make evidence-based shared treatment decisions in real-world clinical care. Donanemab, a monoclonal antibody targeting the insoluble form of β-amyloid found in plaques, significantly slows cognitive and functional decline of AD in participants with mild cognitive impairment (MCI) or mild AD-related dementia. This analysis reviews the efficacy of donanemab across various clinical outcome assessments, using both published data and new complementary analyses to provide context on its potential benefits for patients and caregivers.

METHODS: We present findings from prespecified and post hoc analyses from the TRAILBLAZER-ALZ 2 trial. Clinical outcomes assessed were Integrated AD Rating Scale (iADRS), comprising the 13-item AD Assessment Scale-Cognitive Subscale (ADAS-Cog13) and AD Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL); Clinical Dementia Rating (CDR)-Sum of Boxes (CDR-SB) for clinical severity and individual cognitive and functional domains; CDR-Global for clinical severity stage progression; meaningful within-patient change (MWPC); and ADCS-Activities of Daily Living dependence score.

RESULTS: Donanemab reduced the risk of progression from MCI to mild AD by 33% (hazard ratio [HR] = 0.67; 95% CI 0.52-0.87; p = 0.003) and from mild to moderate AD by 50% (HR = 0.50; 95% CI 0.33-0.78; p = 0.002). In addition, donanemab reduced MWPC risk over 76 weeks by 38% for CDR-SB (HR = 0.62; 95% CI 0.52-0.75; p < 0.001) and 30% for iADRS (HR = 0.70; 95% CI 0.58-0.84; p < 0.001). Donanemab-treated participants exhibited significant slowing of clinical progression across multiple ADAS-Cog13 and ADCS-iADL items and all CDR-SB cognitive and functional domains. Donanemab also slowed progression of dependence least-squares mean change difference, -0.14 [95% CI -0.24 to -0.04; p = 0.007]), representing 23% slowing of progression (95% CI 6.17%-40.32%), and reduced risk of progression to requiring in-home support by 27% (HR = 0.74; 95% CI 0.59-0.91; p = 0.005).

DISCUSSION: These results add to the evidence and further support clinically meaningful donanemab-mediated effects on cognition and function for patients and their caregivers and may aid communication of realistic treatment expectations and informed decision-making.

ClinicalTrials.gov NCT04437511. Submitted: June 17, 2020; First patient enrolled: June 19, 2020. clinicaltrials.gov/study/NCT04437511 EudraCT Number 2020-000077-25. Start date of recruitment: June 19, 2020. clinicaltrialsregister.eu/ctr-search/trial/2020-000077-25/results.},
}

Humans
*Alzheimer Disease/drug therapy
Aged
*Cognitive Dysfunction/drug therapy
Male
Female
*Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology
Aged, 80 and over
Disease Progression
Activities of Daily Living
*Outcome Assessment, Health Care